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WO1997011091A1 - Nouveaux composes peptidiques et leurs compositions medicinales - Google Patents

Nouveaux composes peptidiques et leurs compositions medicinales Download PDF

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Publication number
WO1997011091A1
WO1997011091A1 PCT/JP1996/002697 JP9602697W WO9711091A1 WO 1997011091 A1 WO1997011091 A1 WO 1997011091A1 JP 9602697 W JP9602697 W JP 9602697W WO 9711091 A1 WO9711091 A1 WO 9711091A1
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Prior art keywords
nhco
receptor
amino acid
peptide
side chain
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PCT/JP1996/002697
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English (en)
Japanese (ja)
Inventor
Shiro Kataoka
Tsuyoshi Nishitoba
Motoo Takahashi
Eiji Sawa
Masaru Kamishohara
Original Assignee
Kirin Beer Kabushiki Kaisha
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Application filed by Kirin Beer Kabushiki Kaisha filed Critical Kirin Beer Kabushiki Kaisha
Priority to AU70008/96A priority Critical patent/AU7000896A/en
Publication of WO1997011091A1 publication Critical patent/WO1997011091A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/715—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons

Definitions

  • the present invention relates to a novel peptide compound designed based on the intracellular carboxy terminal sequence of a cell membrane receptor and having an activity of regulating the function of the cell membrane receptor.
  • the present invention further relates to a pharmaceutical composition containing the compound of the present invention.
  • Cell membrane receptors are present on the cell membrane and generate signals ⁇ 1 inside cells when stimulated by the ligand. Cells undergo various changes in response to signals from cell membrane receptors, including proliferation, growth arrest, differentiation, cell death, and production of new cell membrane receptors and cytokines. While control at the cellular level is centralized and individual homeostasis is maintained, abnormalities in signals from cell membrane receptors cause various diseases. For example, in cancer, a gene cloned as a cancer cell often encodes a cell membrane receptor.
  • EGF receptor which is a receptor-type oral synkinase
  • EGF receptor which is a receptor-type oral synkinase
  • cytokines such as IL-14 and IL-5 may cause elimination, ie, enhancement of signals from IL-4 receptor and IL-15 receptor (M Edd 1 et 0 n et al.
  • the present invention relates to a cell membrane receptor, a C-terminal region involved in intracellular signal regulation.
  • the present invention relates to a novel compound, a pharmaceutical composition containing the compound, and a method for analyzing the function of a receptor using the compound.
  • a compound having an activity of regulating the function of the RCR region of a cell membrane receptor is included in the C-terminal sequence information of the receptor.
  • the compound itself designed based on the above, and a method of analyzing the function of the receptor using the compound are not known at all.
  • the present invention also relates to a method for analyzing the function of the C-terminus of a receptor.
  • Conventional techniques in the art employ a deletion or substitution at the C-terminus of the receptor and transfer of the mutant receptor to the cell.
  • the function of the C-terminus of the receptor was introduced. There is no known method of analysis.
  • the present invention also relates to a method for regulating the signal of a cell membrane receptor by inhibiting the binding between the C-terminus of the cell membrane receptor and its binding white.
  • the compound of the present invention can be effectively used as an inhibitor. It should be noted that, as far as the present inventors know, the method of regulating the signal of the cell membrane receptor by inhibiting the binding between the C-terminus of the cell membrane receptor and its binding protein is not known at all.
  • Fas is a receptor present on the cell surface and belongs to the TNF receptor superfamily (Smith et al., Cell 76: 959-962, pp. 1994). It is known that Fas has a function of transmitting a signal of cell death to cells when a Fas ligand or an anti-Fas antibody binds to its extracellular region and inducing apoptosis in cells (Itoh et al., Cell 6 Volume 6, 2 3 3—2 4 3 pages, 1 9 1991; Suda et al., Cell 75, 1169-1178, 1993).
  • the Fas ligand is expressed on cytotoxic T cells, and it is known that a Fas-mediated system can be used to attack target cells (Lowin et al., Nature 370, 650-652). Page, 1994). Fiber that expresses F a is widespread
  • a technique for inducing apoptosis in cancer cells by stimulating antibodies against Fas or the like has been known.
  • the effect of Fas-mediated cell death on cancer cells in vivo has been reported to reduce B cell lymphoma by administering anti-Fas antibody to nude mice transplanted with B cell lymphoma (Trauth et al.). Science 245, 301-305, 1989).
  • Fas Cells that have Fas do not always induce cell death with the Fas ligand ⁇ anti-Fas antibody, and many cancer cells that express Fas but do not induce apoptosis have been reported. Thus, stimulation of antibodies against Fa s is ineffective for those cancer cells (Wong et al., J. Immunol. 152, 1751-1755, 1994).
  • Mutant Fas which lacks the C-terminal 15 amino acid residues of Fas, has an enhanced ability to transmit cell death compared to normal Fas.Fas C-terminal 15-amino acid 3 ⁇ 4S is mediated by Fas It is known to be a regulatory region of cell death (Itoh et al., J. Biol. Chem. 268, 10932-10937, 1993).
  • PTP-BAS binds to a region containing the C-terminal 15 amino acids of Fas in cells and negatively regulates the cell death signal via Fas (Sato et al., ⁇ 3 ⁇ 4).
  • PTP-BAS was discovered as a tyrosine dephosphorylating enzyme (liaekawa et al., FEBS Lett. 337, 200-206, 1994).
  • PTP—BAS is also known by the discoverers as h PTP 1 E, PTP L1 (Banville et al., J. Biol. Chem. 269, 22320—22327, 1994; Saras et al., J. Biol. Chem. 269, 24082-24089, 1994) o
  • PTP-BAS is most strongly expressed in the kidneys and lungs of adult humans, and is also expressed in the brain, heart, kidney, and placenta. Little expression is observed in the large intestine, peripheral blood, liver, and skeletal muscle (Maekawa et al .; Banville et al., Supra; Saras et al., Supra). The significance of expression in each of these tissues is not clear.
  • a method of killing cancer cells using a compound targeting PTP-BAS has not been known so far as far as the present inventors know. It has been reported that the 15-amino acid sequence near the C-terminus of Fas is important for the interaction between Fas and PTP-BAS (Sato et al., Supra; Cleveland et al., Cell 81, 479). — P. 482, 1995), but no compound that inhibits their interaction has been known so far to the present inventors' knowledge.
  • Va s o a c t i v e Int e st e t i na l P e p t i d e (V I P) is a neuropeptide consisting of 28 amino acids, and P i t u i t a r y
  • PACAP secretin, glucagon, calcitonin, parathyroid hormone, etc.
  • VIP has the function of relaxing smooth muscle and increasing blood flow. It regulates the flow of water and ions from the lung and intestinal epithelium, regulates the growth and survival of neurons, and affects many immune functions.
  • the high-affinity receptor selective for VIP is expressed in gods; ⁇ , cells of a subset of the respiratory, gastrointestinal, and immune systems.
  • Human high affinity type IV I P receptor is expressed in gods; ⁇ , cells of a subset of the respiratory, gastrointestinal, and immune systems.
  • HVR1 The endogene has been cloned from human colon cancer cells HT-29, and its chromosome expression has also been obtained (C0uVineau et al., Biochem.
  • HVR1 belongs to the GPC R family and has a seven-transmembrane structure. HVR1 is most strongly expressed in human lung, and is also expressed in pre-ffl3 ⁇ 4, peripheral blood cells, liver, brain, small intestine, etc.
  • HRVRlilfei VIP antagonist suppressed the growth of non-small cell lung cancer (Mody, et al., Pro. Natl. Ad. Sci. USA 90, 4345-4349, 1993). Is present on the short arm of human chromosome 3 involved in small cell lung cancer
  • ADRENERGIC receptor Conventionally, mainly by pharmacological standards, alpha 2 ⁇ beauty / S i,; have been classified into 9 0 receptor subtypes. yS-adrenergic receptor One is expressed by subtype and its physiological role is different. S ⁇ is present in the heart, adipose tissue, and cerebral cortex. Its activation is heartbeat increase, cardiac contractility increase, and lipolysis. Is induced. / 9 2 lung, liver, J ,, brain, smooth muscle, skeletal muscle, and present in polymorphonuclear cells, causing a relaxation of the gas tube ⁇ and vascular smooth muscle. Since the physiological functions of each receptor are different, specific inhibition is required for each receptor.
  • the ⁇ 2 - ⁇ drainage receptor is a receptor belonging to the GPCR family cloned in 1987 (Ko bilka et al., J. Biol. Chem. 262, 7321-7327, 1987).
  • the jS Q -adrenagic receptor is known to activate adenylate cyclase via a G protein. It has been reported that the vicinity of the intracellular C-terminal region of the / So-adrenergic receptor is related to homogenous desensitization.
  • Intracellular signal of ⁇ 2 -drainage receptor An agent that selectively acts on the fel system has not been known so far as far as the present inventors know.
  • Interleukin-8 is a 72 amino acid peptide with a molecular weight of 8 kDa, which is produced by various cell types upon activation by interleukin-1 and other stimulatory cytokines (Westwick et al. ,
  • IL-18 promotes neutrophil chemotaxis and degranulation.
  • IL-8 is a potential neutrophil inducer in vitro and has been shown to have potent inflammatory effects in vivo.
  • various inflammatory ⁇ B patients have IL-8 IL-18 is involved in diseases such as rheumatoid arthritis, gout, neutrophilic dermatitis, asthma, nausea ⁇ ! Inflammation, »disease, adult respiratory distress, and white ifil This has been clarified. Therefore, it is expected to be an inhibitor of IL-18 action or a useful anti-inflammatory agent.
  • the IL-18 receptor is a glycoprotein belonging to the GPCR family with a molecular weight of about 60 kDa and was cloned in 1991 (Holmés et al.,
  • the IL-8 receptor is known as type A or type B, and cells expressing type A and type B are different.
  • Type A is a PHA-stimulated T cell
  • the cells are expressed in a wide range of cells such as cells, monocytes, synovial cells, and neutrophils.
  • type B is mainly expressed in neutrophils.
  • the expression of the IL-18 receptor is markedly increased (Kemeny et al., Int. Arch. Arlgy Immu no 1. 104, 317-322, 1994). It has been reported that administration of anti-IL-8 antibody can suppress proteinuria in a gastritis model
  • the G protein is bound to the intracellular region of the IL-18 receptor, and it has been reported that G protein is involved in signal transmission (Kupper et al., Biochem. J. 282, 429-434. , 1992). However, it has not been known that the intracellular C-terminal region of the IL-18 receptor affects its function as far as the present inventors know. Further, a drug that selectively acts on the intracellular signal fi system of the IL-18 receptor has not been known so far as far as the present inventors know.
  • the present invention provides a design based on the intracellular carboxy terminal sequence of a cell membrane receptor. It is an object of the present invention to develop a novel compound having an activity of regulating the function of the ⁇ ffl cell membrane receptor. Another object of the present invention is to develop a novel drug containing the novel compound. Still another object of the present invention is to provide a method for analyzing the function of the C-terminus of a cell membrane receptor using the novel compound.
  • Still another object of the present invention is to provide a method for regulating a signal fe of a cell membrane receptor, and a method for treating a disease relating to signal transmission of a cell membrane receptor.
  • peptides having a FasOC terminal sequence and derivatives thereof inhibit the activity of inhibiting the binding between Fas and PTP-BAS. And found that they positively regulate their cell death signal. That is, a peptide unit essential for inhibiting the binding of Fas to PTP-BAS was determined, and when a derivative thereof was allowed to act on pain cells, it was found that this enhances the cell death signal caused by Fas. Was.
  • the present inventors have found that a peptide derivative having a C-terminal sequence of this receptor suppresses the function of VIP receptor with respect to a VI-P receptor belonging to a completely different receptor family from Fas.
  • the present inventors have also proposed peptide derivatives, which are different from the Fs and VIP receptors and have different C-terminal sequences from the ⁇ -terminal drainage receptor and the IL-18 receptor, based on their C-terminal sequences. It was found to have some effect on the function of the receptor. That is, the peptide derivative having the C-terminal sequence of 0 -adrenergic receptor inhibits bronchial relaxation induced by isoproterenol, which acts agonistically on ⁇ 2 -adrenergic receptor.
  • Peptide derivative with C-terminal sequence of receptor is IL It was found to selectively inhibit the intracellular uptake of calcium induced by (18).
  • the above four receptors have the common feature that the third amino S ⁇ group from the C-terminal is serine or threonine.
  • the present inventors further obtained a GIP software package (manufactured by Genetics Computer Group) for the group of receptors having the characteristics, searched the PIP-Protein database, and identified the C-terminal sequence. And the results in the table below were obtained.
  • a receptor having such characteristics is referred to as a receptor having a tSXX motif.
  • S represents serine or threonine
  • each X represents any amino acid.
  • tSXX motif In the RCR region of the cell membrane receptor, a series of sequences in which the third amino acid from the C-terminus is serine or threonine is referred to as a tSXX motif as described above in the present invention. Those with palin are called tSXV motifs, and those with leucine are called tSXL motifs. Hereinafter, it is similarly referred to by the C-terminal amino acid.
  • the present invention provides derivatives of peptides, and pharmaceutically acceptable salts thereof.
  • the present invention also provides a pharmaceutical composition containing these compounds.
  • the present invention provides a method for analyzing the C-terminal function of a cell membrane receptor using these compounds.
  • the present invention also provides a method for regulating a signal of a cell membrane receptor by inhibiting the binding between a C-terminus of a cell membrane receptor and its binding protein, and a method for treating a disease relating to signal transduction of a cell membrane receptor. Is what you do.
  • the compounds of the present invention are quite different from their corresponding cell membrane receptors: ⁇ , and are compounds that have the activity to modulate the signal from the corresponding receptor by competing with the C-terminus of the corresponding receptor.
  • “having an activity of regulating a signal from a receptor” means “having an activity of inhibiting or enhancing a signal from a receptor”.
  • the term “inhibition” as used herein means any degree of inhibition, and is not necessarily limited to complete inhibition is not.
  • FIG. 1 is an autoradiogram showing the inhibition of Fas / PTP-BAS binding in vitro by the C-terminal 15 amino acid peptide of Fas.
  • FIG. 2 is a graph showing the effect of Cs-terminal peptides of Fas of different lengths on the binding of FasZPTP-BAS in vitro.
  • FIG. 3 is a graph showing the in vitro inhibition of F as / PTP-BAS binding in the presence of the scanned peptide ImM, in which each amino acid of Ac-SLV is replaced with another L-amino acid or glycine.
  • FIG. 4 is a graph showing in vitro inhibition of F as / PTP-BAS binding in the presence of the scanned peptide 0. ImM, in which the amino acid is replaced by glycine and the other amino acid is replaced by glycine.
  • FIG. 5 is a graph showing a concentration-dependent curve of inhibition of Ac-SLV and Ac-TLV in vitro Fast / PTP-BAS binding.
  • FIG. 6 is a graph showing the in vitro F azZPTP-BAS binding inhibitory activity of D-, N-methyl, and reduced peptides.
  • FIG. 5 is a graph showing the dependence curve of the N-terminal modification for inhibition of in vitro FazZPTP-BAS binding.
  • FIG. 8 is a graph showing the in vitro F azZPTP-BAS binding inhibitory activity of the modified C-terminal.
  • FIG. 9 is a photograph of a morphology of an organism showing the cell death-inducing effect of Ac-SLV injected into human colorectal cancer DLD-1 cells by microinjection.
  • the arrow indicates a typical apoptotic image.
  • Figure 10 shows the results for Cyh-NHCO-SLV-OMe, Cyh-NHCO-SLV-OEt, Ph-NHCO-SLV-OMe, and Ph-NHCO-SLV-OEt.
  • 1 is a graph showing the cell death-inducing effect on human colon cancer cells DLD-1.
  • FIG. 11 is a photograph of an organism showing the cell death-inducing effect of Ph-NHCO-SLV-OEt on human: ⁇ cancer cell DLD-1.
  • FIG. 12 is a graph showing the effect of Ph-NHCO-SLV-OEt on VIP-dependent bronchial relaxation.
  • FIG. 13 is a graph showing the effect of Ph-NHCO-SLA-OEt on VIP-dependent bronchial relaxation.
  • FIG. 14 is a graph showing the effect of Ph-NHCO-SLL-OEt on VIP-dependent bronchial relaxation.
  • FIG. 15 is a graph showing the effect of Ph-NHCO-SLV-OH on VIP-dependent bronchial 3 ⁇ 4 ⁇ .
  • FIG. 16 is a graph showing the effect of Ph-NHCO-SLL-OEt on ISO-dependent bronchial relaxation.
  • FIG. 17 is a graph showing the effect of Ph-NHCO-SLA-OEt on ISO-dependent bronchial relaxation.
  • FIG. 18 is a graph showing the effect of Ph-NHCO-SLV-OEt on ISO-dependent bronchial relaxation.
  • the compounds of the present invention are designed based on the C-terminal sequence of a cell receptor having a signal regulatory region (RCR region) in the C-terminal region, and regulate the signal from the receptor by competing with the C-terminal of the receptor. , Its peptide derivatives and their salts.
  • the peptide, its peptide derivative and their salts according to the present invention may be hydrated. More specifically, the compound of the present invention has the activity of binding to the C-terminal end of the receptor, or Or at least three that have the activity of regulating the function of a cell membrane receptor in which the amino acid sequence at the intracellular carboxy terminus is 1 A-1 A 2 -A 0 , including when the receptor c ⁇ binding protein is unknown.
  • X a i or amino acid belonging to the same classification and Hache
  • Y L-amino acid or glycine
  • Zeta Alpha lambda or a 3 And a carboxy terminal of the same class.
  • the compound of the present invention specifically includes, for example, at least three amino acids that inhibit the binding between Fas having a C-terminal sequence of —S-L-V and PTP-BAS.
  • the compound of the present invention preferably has 3 to 8 amino acids in the length direction.
  • FasZPTP-BAS binding inhibitor ⁇ has the same activity as 15 peptides if there are 6 peptides in the length direction. It has been confirmed that if there are three in the length direction, they have the same S activity as four and five.
  • - ⁇ the shorter the peptide chain length, the easier it is for the peptide to be incorporated into the biological fiber, resulting in an increase in the number of incorporated peptides.
  • Biologically invalid! It is preferable that the peptide chain length of the compound of the present invention is 3 because the force of reading is reduced.
  • Y D-amino acid
  • glycine L-amino acid or It is preferably glycine (however, the activity is not significantly affected by the ⁇ ⁇ of the amino acid residue.
  • the present invention also relates to peptide derivatives that are metabolically stable in cells (ie, have excellent biological stability) and have superior receptor signal-modulating activity.
  • the present inventors have proposed the pharmacology of a peptide having FasZPTP-BAS binding inhibitory activity.
  • a marked enhancement of the above-mentioned activities was observed in compounds in which the N-terminal amino group was modified with hydrophobicity. was found to be.
  • Such a compound is represented by the following formula 4:
  • R A or the side chain structure of an amino acid belonging to the same class as A;
  • R. Side-chain structure or hydrogen of L-amino acid
  • R. Mean side chain structure of Amino acids belonging to A 3 or A 3 and same classification
  • R 4 is the side chain structure of any of Amino acids
  • R P is linear to C 6 substituted or unsubstituted
  • R 6 is independently hydrogen or methyl
  • each R 7 is independently hydrogen or oxygen
  • B is carbonyl or straight-chain.
  • R 8 and R 9 are each hydrogen, or a substituted or unsubstituted alkyl group, or a S-substituted or non-S-substituted aromatic group, wherein the alkyl group is a straight chain, branched chain, or cyclic.
  • m is 0 to 12, n is 0 or 1, and when n is 1, R n and R 9 may be united to form a ring; provided that R and R g Is not hydrogen at the same time].
  • R 1 side chain structure of L-serine or L-threonine
  • R 2 side chain structure of L-amino acid or hydrogen
  • R 3 side chain structure of L-amino acid or hydrogen.
  • R i side chain structure of L-serine or L-threonine
  • R o L-side chain structure of amino acid
  • R 5 Side chain structure of L-valine, L-isoleucine or L-mouth isin, R 5 , R.
  • R 0 have the same meanings as described above.
  • R 9 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aromatic group.
  • the alkyl group is linear, branched or cyclic, and is more preferable in the above i4. More specifically, there can be mentioned a modified group of peridoside having a hydrophobic substituent in which is 1 and B is a carbonyl group. Specific examples of preferred substituents located at the N-terminus of these compounds are acetyl groups, more preferred are substituted or unsubstituted cycloalkylaminocarbonyl groups, and substituted or unsubstituted phenyl groups.
  • Examples include a minocarbonyl group and a substituted or unsubstituted cyclic aminoamino group.
  • cycloalkyl and C-amino as described herein mean a 3- to 8-membered cyclic structure.
  • esterification of the carboxyl group at the C-terminus is expected to increase the uptake of these derivatives into biological tissues due to increased hydrophobicity.
  • Examples of such a compound include compounds in which, in the above description, is substituted or unsubstituted, and is a straight-chain, branched-chain, or cyclic alkoxy group.
  • the compound of the present invention includes a biologically modified form of the binding-inhibiting peptide, for example, a modified form thereof for stability in the body, for example, a substituted form with a D-amino acid, a substituted form with ⁇ -methylamino acid, or an amide bond. And the reductant thereof.
  • a biologically modified form of the binding-inhibiting peptide for example, a modified form thereof for stability in the body, for example, a substituted form with a D-amino acid, a substituted form with ⁇ -methylamino acid, or an amide bond.
  • the reductant thereof Specifically, in the above formula, a compound in which at least one of R is a methinole group, or a compound in which at least one of the carbons having R, or in the side chain has an S configuration or an R configuration, or Compounds in which at least one of R 7 is less than hydrogen can be given. These modifications have the activity of inhibiting the binding of Fas to PTP-
  • N-terminal or C-terminal modifications are effective not only in the FasZPTP-BAS binding inhibition system, but also in the receptor signal regulation system using other cells or tissues.
  • the N-terminal is phenylaminocarbonylated and the C-terminal is esterified. Some compounds showed activity.
  • the present invention also relates to a method for regulating the signal of a cell membrane receptor by inhibiting the binding of the C-terminus of the cell membrane receptor to its binding protein, and a method for treating a disease relating to signal transduction of the cell membrane receptor.
  • the Specific examples include a method for inducing cell death in cancer cells by inhibiting the binding of Fas to PTP-BAS, and the use of a compound for inducing cell death in chemotherapy. be able to.
  • the present inventors have found that the expression of PTP-BAS is remarkably increased from the normal level in certain types of cancer cells. Therefore, by adding FasZPTP-BAS binding inhibitor of the present invention, It was found that the sensitivity of cancer cells to anti-Fas antibody could be increased. These findings indicate that the Fas / PTP-BAS binding inhibitor of the present invention is effective for cancer chemotherapy. Cytotoxic T cells expressing the Fas ligand are present in the organism, and therefore, the inhibitor of the FasZPTP-BAS binding inhibitor of the present invention can be used only to release the suppression of the cell death signal to produce cancer. It is possible to induce cell death.
  • the present invention includes, but is not limited to, a method of inducing cell death in cancer cells, which comprises administering the compound of the present invention alone to a cancer patient.
  • This also includes the above method used in combination with antibodies and Fas ligands.
  • the dose of the compound used at that time the ability to bind to BAS-Fas is reduced or completely inhibited. Decreasing the binding activity of PTP-BAS to Fas by adjusting the dose of the compound is a potential adverse side effect. It is effective to eliminate the effect.
  • the compounds of the present invention are effective as inhibitors of the binding of PTP-BAS, a protein phosphatase, to F as.
  • PTP-BAS Strongly recognizing peptides, as is apparent from the reference examples described below, the compounds of the present invention have fewer side effects than general protein dephosphorylation inhibitors. It is presumed that there is.
  • amino acid is represented by one-letter resentment as shown below.
  • the symbol (X) is used to indicate any amino acid or amino acid residue.
  • the classification of amino acids is determined by the hydrophobicity, hydrophilicity, charge, and hydrogen bond of the side chain on the ⁇ -carbon as follows:
  • One amino acid is classified by the physical and chemical properties of the side chain. It belongs to the classification of power river power. That is, the term “amino acids belonging to the same class” in the present invention includes a case where a plurality of classes of amino acids are referred to simultaneously.
  • the “amino acid” in the present invention is not limited to natural amino acids, but also includes non-natural amino acids.
  • Non-natural amino acids include, for example, homoserine, / 9-hydroxyvaline, 0-4-hydroxyphenyltyrosine, ⁇ -t-butylglycine, 2-aminoaminoacid, ⁇ -cyclohexylglycine, and ⁇ -phenylglycine. I can give it.
  • Hydrophobic amino acids A, R, N, Q, E, I, K, M, F, P, W, Y, V ⁇ -amino acids: R, N, D, C, Q, E, H, K, S, T, Y
  • substituents other than amino acids include acetyl group (Ac), methyl group (Me), ethyl group (Et), isopropyl group (iPr), and phenyl group.
  • (Ph) is represented by a cyclohexyl group (Cyh).
  • Ac-TXA-OEt Ac-TXC-OEt, Ac-TXD-OEt, Ac-TXE-OEt, Ac-TXF-OEt, Ac-TXG-OEt, Ac-TXH-OEt, Ac-TXI-OEt, Ac-TXK-OEt, Ac-TXL-OEt, Ac-TXM-OEt Ac-TXN-OEt, Ac-TXP-OEt, Ac-TXQ-OEt, Ac- TXR-OE "Ac-TXS—OEt, Ac-TXT-OEt, Ac-TXV-OEt, Ac-TXW-OEt Ac-TXY-OEt.
  • Ph—NHCO—TXA Ph—NHCO—TXC, Ph—NHCO—TXD, Ph—NHCO—TXE, Ph—NHCO—TXF, Ph—NHCO—TXG, Ph—NHCO—TXH, Ph—NHCO—TX K
  • Ph— NHCO-TXK Ph-NHCO-TXL, Ph-NHCO-TXM, Ph-NHCO-TXN, Ph-NHCO-TXP, Ph-NHCO-TXQ, Ph-NHCO-TXR, Ph-NHCO-TXS, Ph-NHCO- TXT, Ph-NHCO-TXV, Ph-NHCO-TXW, Ph-NHCO-TXY.
  • Ph—NHCO—SXA—OE t Ph-NHCO-SXC-OE t Ph— NHCO-SXD-OEt, Ph-NHCO-SXE-OEt, Ph-NHCO-SXt-Ph-NHCO-SXG-OEt, Ph-NHCO-SXH-OEt, Ph-NHCO-SXI -OE t, P h -NH C 0-S XK-0 E t, Ph-NHCO-SXL-OE t. P h -NH C 0-S XM- 0 E t.
  • Ph-NHCO-TXA-OEt Ph-NHC 0-TXC-0Et, Ph-NHCO-TXD-OEt, Ph-NHCO-TXE-OEt, Ph-NHCO-TXF-OEt, Ph-NHCO-TXG-OE t, Ph-NHCO-TXH-OE t, Ph-NHCO-TX I-OE t, Ph-NHCO-T XK-0 Et, Ph-NHCO-TXL-OE t.
  • Ph-NH C 0-TXM-0 Et Ph-NHCO-TXN-OE t, Ph-NHCO-TXP-OE t, Ph-NHCO-TXQ-OE t, Ph-NHCO-TXR-OE t, Ph-NHCO-TXS-OEt, Ph-NHCO-TXT-OEt, Ph-NHC0-TXV-0Et Ph-NHCO-TXW-OEt, Ph-NHCO-TXY-OEt.
  • Cy h-NHCO-SXV Cyh-NH C0-TXV, Cy h-NHCO-SXI, Cy h-NHCO-TX IC yh-NHC 0-SX and Cyh-NHCO-TX Cy h-NHCO- SXV-OEt, Cyh-NHCO-TXV-OEt, Cyh-NHCO-SXI-OEt, Cyh-NHCO-TXI-OEt, Cyh-NHCO-SXL-OEt, Cyh-NHCO-TXL- OE to (2) t SLV
  • Ph-NHCO-S LV Ph— NHCO-CLV, Ph-NHC0-TLV o e) N-terminal phenylaminocarbonyl, C-terminal estenole:
  • D body Ac-(D) SLV, Ac- (D) SL V-OMe 0
  • Ph-NHCO-S AV-OE t Ph-NH C 0-SCV-0 Et, Ph-NHCO-SDV-OE t, P h-NHCO-SEV-OE t, Ph-NHCO-SFV-OE t , Ph—NHCO—SGV—OEt, Ph—NHCO—SHV—OEt, Ph—NHCO—SIV—OEt, Ph—NH C0—SKV—0Et, Ph—NHCO—SMV—OEt, P h -NH C 0- SN V-0 E t, Ph-NHCO-SPV-OE t, Ph-NHCO-SQV-OE Ph-NHCO -SRV-OE t Ph— NHCO-S SV— OE t :, Ph — NHCO— STV-OE t, Ph-NHCO-S VV-OE t P h-NH C 0-S WV- 0 E t, Ph— NHCO-S YV— OE t, P h-NH
  • Ph-NHCO-S CL-OE t P h-NHC 0-SFL-0 E t, Ph-NHCO-SGL-OE t, Ph -NHCO-SHL-OE t Ph-NHCO-I SLL-OE t, Ph- NHCO-S SL-OE t, Ph-NHCO-SVL-OE t, Ph-NHCO-SYL-OE t.
  • Ph-NHCO-TVL-OE t Ph-NHCO-S LL-OMe ⁇ Ph-NHCO -SL L-0 i P r P h— NH C 0— TT L-OM e, Ph— NHCO— TTL-0 i Pr.
  • Ac-SDC Ac-SLC, Ac-SMC, Ac-SSC, Ac-STC, Ac-SVC, Ac-TDC, Ac-TEC, Ac-TGC.
  • Ph-NHCO-SDC-OE t P h-NH C 0— SLC— 0 Et, Ph—NHCO—SMC—OE t, Ph—NHCO—SSC—OE t, Ph—NHCO—STC—OE t, Ph— NHCO— S VC- OE t, P h-NHCO-TDC-OE t, P h-NHCO-TE C-OE t, P h -NH C 0-TGC-0 E t c
  • Ph-NHCO-SHF Ph-NHCO-SVF
  • Ph-NHCO-TCF Ph-NHCO-TCF
  • Ph-NHCO-TTF Ph-NHCO-TYF.
  • Ph-NHCO-SEK Ph-NHCO-SGK, Ph-NHCO-SPK, Ph-NHCO-SSK, Ph-NHCO-TEK, Ph-NHCO-TIK, Ph-NHCO-TSK, Ph-NHCO-TTK.
  • Ph—NHCO—SEK—OEt Ph—NHC 0—SGK—0Et :, Ph-NHCO-S PK-OE t Ph-NHCO-S SK-OE t. Ph-NHCO-TEK-OE t, Ph-NHCO-TIK-OE t, Ph-NHCO-TSK-OE t, Ph-NHCO-TTK-OE t.
  • Preferred compounds of the present invention include Ac—SLV, Ac—SFV. Ac—SIV, Ac—SRV, Ac—SVV, Ac—TLV, Ac—SLL, Ac—TTL, Ac—SLV—OME, Ac—SFV— OMe, Ac— SIV— OMe, Ac— SRV— OMe, Ac— SVV— OMe, Ac— TLV— OMe, Ac— SLL—OMe, Ac—TTL—OMe, Ac—SLV—OEt, Ac—SFV—OE t, Ac— SIV— OE t, Ac-SRV— OE t, Ac— SVV— OE t, Ac— TLV— OE t, Ac— SLL— OE t, A c-TTL-OE t, Ph-NHCO-SLV Ph—NHCO—SFV, Ph-NHCO-S I V.
  • Ph—NHCO—SRV Ph—NHCO—SVV
  • Ph—NHCO—TLV Ph—NHCO—SLL
  • Ph—NHCO—TTL Ph—NHCO—SLV— OMe
  • Ph-NHCO-S FV-OMe Ph-NHCO-S I V-OMe.
  • Ph-NHCO-SRV-OMe Ph-NHC 0-SVV-OM e, Ph-NHCO-TL V-OMe, Ph-NHC 0-SLL-OM e, Ph-NHCO-TTL-OMe, Ph- NHCO—SLV—OE t, P h-NHCO-S FV—OE t, Ph—NHCO—SIV—OE t, P h—NH CO—S RV—OE t Ph—NHCO—S VV—OE t, P h — NH C 0— TLV— 0 E t, Ph—NHCO-SLL-OE t P h— NH C 0—TT L—1 0 E t, C y h—NHCO—SLV, Cy h—NHCO—SFV, C yh — NH C 0-SIV, Cy h-NHCO-SRV, Cy h-NHCO-S VV, Cy h-NHCO- TLV, Cy h-NHCO-S LLC yh
  • Cyh-NHCO-SIV-OMe Cyh-NHCO-SRV-OMe, Cyh-NHCO-S VV-OMe, Cyh-NHCO-TL V-OMe, Cyh — NHCO-SLL— OMe, C yh— NH C 0— TT L-OM e, Cyh— NHCO-SLV-OEt, Cyh— NHCO-SFV-OEt, Cyh-NHCO— SIV— OEt, Cyh- NHCO-SRV—OE t, Cyh-NHCO-SVV-OE t, Cy h-NHCO-TLV-OE t, Cyh-NHCO-SLL-OE t Cyh-NHCO-TTL-OE t.
  • Ac—, Ph—CO—, Cyh—CO—, Ph—NHCO—, and Cyh—NHCO— represent N-terminal modifying groups, and are acetyl group, It means a phenylcarbonyl group, a cyclohexylcarbonyl group, a phenylaminocarbonyl group, and a cyclohexylaminocarbonyl group.
  • one OMe, one OEt, and --0iPr are C-terminal carboxyls, respectively. It means that the sil group is methyl-esterified, ethyl-esterified and isopropyl-esterified.
  • One ⁇ — (CH 2 NH) in the sequence means that the carbonyl group of the amide bond is reduced, and one (NM e) X means that the amino group of the amino acid is methylated.
  • Means The D amino acid in the sequence is represented by the symbol (D) X.
  • the peptides in the present invention can be synthesized by a conventional solid phase synthesis method, a liquid phase method, or a combination of the two methods described in the following books: Haruaki Yajima (eds.) , Vol. 14, Hirokawa Damaged Store; Kiyofumi Ekenbara, Journal of Organic Synthetic Chemistry, Vol. 52, pp. 347, 1991; or Gregory A.
  • RSynthetic Peptides A User's Guide, WH Freeman and Company.
  • the peptide synthesized on the solid phase can be obtained by modifying the N-terminus as necessary after the final deprotection of ⁇ S, and then cleaving from the solid phase (resin).
  • Peptides and their modifications are identified and structurally confirmed by mass spectrometry (ion spray MS, FAB-MS, FD-MS), HPLC, and NMR (500 MHz) spectra. I went in.
  • acetylation can be obtained by treatment with anhydrous acetic acid in DMF (dimethylformamide).
  • DMF dimethylformamide
  • other acylated derivatives can be obtained by condensing a carboxylic acid compound with an N-terminal amino group in the same manner as in peptide synthesis, or by an acid anhydride method in the same manner as in acetylation.
  • ureide-type modification can be obtained by reacting with an isocyanate compound in a polar solvent such as DMF.
  • peptides and their derivatives synthesized on the solid phase can be derived from the solid phase and then converted to a methyl ester by treatment with methanol hydrochloride or diazomethane.
  • an appropriate acid such as hydrogen chloride It is prepared by conducting a condensation reaction with an alcohol compound in the presence.
  • a compound characterized in that one or more of its amide bonds have been reduced is described in "J. Med. Chem.” It can be prepared by the 3 ⁇ 4S method according to the method described on page 874 (1989) or “Japanese Patent Application Laid-Open No. 5-271732”. That is, the compound is reductively alkylated using an aldehyde prepared by the method described in the literature (Org. Syn., 67, 69, 1988). Or by reducing the amide portion with borane.
  • Pharmaceutically acceptable salts of the compounds of the present invention include, for example, alkaline metals such as sodium and potassium, alkaline earth metals such as calcium or magnesium, or dibenzylethylenediamine, triethylamine and the like. It is prepared by treating a compound of the present invention containing an acidic residue with an appropriate amount of an organic base, such as piperidine, or ammonium hydroxide.
  • alkaline metals such as sodium and potassium
  • alkaline earth metals such as calcium or magnesium
  • dibenzylethylenediamine, triethylamine and the like It is prepared by treating a compound of the present invention containing an acidic residue with an appropriate amount of an organic base, such as piperidine, or ammonium hydroxide.
  • Compounds of the present invention having a basic residue include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and sulfamic acid, and formic acid, acetic acid, propionic acid, vivalic acid, getylacetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, dalconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene By reacting with organic acids such as sulfonic acid and lauryl sulfuric acid, the! It can lead to a salt that is acceptable.
  • organic acids such as sulfonic acid and lauryl sulfuric acid
  • the compounds of the present invention have an activity to regulate the function of the C-terminus of the receptor (the function of the RCR region). These compounds are useful as medicaments for mammals, especially for humans.
  • the compounds of the present invention may cause abnormal signal transmission from the receptor by abnormal expression of the receptor or abnormal expression of the ligand. It is useful as a medicament for diseases such as diseases caused by abnormalities in diseases that cause the intracellular receptor to give rise to a signal. For example, if the receptor
  • the corresponding compound of the invention can be administered to the patient for use in treating cancer.
  • types of cancer that can be treated with the compound of the present invention include colorectal cancer, stomach cancer, liver cancer, white,? ⁇ , including but not limited to ovarian cancer.
  • the receptor is a VI ⁇ receptor
  • the corresponding compound of the invention may be administered to a patient for use in the treatment of cancer.
  • examples of the type of cancer that can be treated with the compound of the present invention include, but are not limited to, lung cancer. If the receptor is yS 2 over ⁇ Dre nadic receptors, the compounds of the corresponding present invention can be administered to patients for use in the treatment of glaucoma.
  • the corresponding compound of the present invention can be used to reduce inflammation such as rheumatoid arthritis, gout, neutrophilic dermatitis, asthma, nausea colitis, sepsis, and adult respiratory signs. It can be administered to patients for use in treating ⁇ B.
  • examples of the type of inflammation that can be treated with the corresponding compound of the present invention are not limited to these.
  • the compounds of the present invention corresponding to these receptors and their pharmaceutically acceptable salts can be used for chemotherapeutic use. They can provide a pharmaceutical composition as an antitumor agent.
  • Ras luteinizing hormone-choriogonadotropin receptor 1, T-cell surface glycoprotein CD2, CTLA-4 counter-receptor B7-2, interleukin-5 receptor , G protein-coupled receptor BLR, leukocyte surface glycoprotein CD16, vasoactive intestinal peptide receptor, antigen CD97, cell adhesion receptor CD36, IgG Fc receptor Ila, bradykinin B2 receptor or
  • histamine H2 receptor histamine H2 receptor.
  • the compounds of the present invention corresponding to these receptors, and their pharmaceutically acceptable salts, may provide a medicinal product for the treatment of immune and allergic diseases.
  • nbronectin receptor alpha chain insulin-like growth factor I receptor, antigen CD97, cell adhesion receptor CD36, G-CSF receptor D7 or u-plasminogen activator receptor form 2 can be used.
  • the compounds of the present invention corresponding to these receptors, and their pharmaceutically acceptable salts, can provide a medicament as a therapeutic agent for blood.
  • Cell membrane receptors with tSXX motifs associated with inflammation in addition to IL-8 receptor transforming growth factor beta receptor III, prostaglandin E receptor subtype EP3C, prostanoid IP receptor,
  • prostaglandin E receptor subtype EP1 G protein-coupled receptor BLR, nerve growth factor receptor homo log, TGF-beta typr II receptor, cel l surface glycoprotein C 11c, secretory phospho lipase A2 receptor Bradykinin B2 receptor or histamine H2 receptor can be mentioned.
  • the compounds of the present invention corresponding to these receptors, and their pharmaceutically acceptable salts can provide a pharmaceutical composition as a therapeutic agent for inflammatory diseases including inflammation.
  • the compounds of the invention corresponding to these receptors, and their pharmaceutically acceptable Can
  • Glutamate receptor 6 kainate-preferring receptor, oxytocin receptor, insulin- like growth factor I receptor, protein- tyrosine kinase sky, somatostatin receptor 4, somatostatin receptor I, somatostatin receptor SSTR3, glutamate receptor GluRl, metabotropic glutamate receptor 5 B, metabotropic glutamate 5 A, G protein-coupled receptor GPR1, muscarinic acetylcholine receptor M3, thyropin-releasing hormone receptor, nerve growth factor receptor low affinity, VIP receptor, serotonin receptor 5HT- 2, serotonin receptor 5HT-1C, NMDA receptor chain 1, excitation A receptor modulatory chain hNR2A, corticotropin-releasing hormone receptor, or melanocortin receptor 4.
  • the compounds of the invention corresponding to these receptors, and their pharmaceutically acceptable salts, can provide a pharmaceutical composition for the treatment of the brain and nervous system.
  • Calcitonin receptor arathyroid hormone related peptide receptor or insulin-like growth factor I receptor can be cited as cell membrane receptors having a ts XX motif related to bone diseases 0
  • Compounds of the present invention corresponding to these receptors And their pharmaceutically acceptable salts can provide pharmaceutical compositions for the treatment of bone disease.
  • the compound of the present invention may be administered to a fox, preferably a human, alone or, preferably, in accordance with standard pharmaceutical practice, with a pharmaceutically acceptable carrier or diluent, optionally with a suitable auxiliary. It can be administered as a pharmaceutical composition in combination with an agent.
  • the pharmaceutical composition can be administered orally or parenterally, such as intravenously, intramuscularly, subcutaneously, intraanally, and topically.
  • the selected compound (activity can be in the form of, for example, a tablet or capsule, or as an aqueous solution or suspension).
  • Carriers used for example, lactose, corn flour, etc., may be used, and a lubricant such as magnesium stearate may be added if desired,
  • lactose as a useful diluent
  • the active ingredient may be mixed with a commonly used emulsifying or suspending reagent.
  • Specific sweetening or flavoring agents can be added
  • sterile solutions of the active ingredients are routinely made Preparation To.
  • the solution containing the active ⁇ is adjusted as appropriate PH, and buffer Should be made.
  • the total solute concentration should be adjusted to make the final preparation isotonic.
  • the present invention is particularly, with a carrier or diluent is pharmaceutically acceptable, without containing or child these, as c such relates to pharmaceutical compositions comprising a compound of the present invention a pharmaceutically effective amount,
  • a carrier or diluent is pharmaceutically acceptable, without containing or child these, as c
  • pharmaceutical compositions comprising a compound of the present invention a pharmaceutically effective amount
  • the compounds of the present invention for example, those in the form of an aqueous solution containing, for example, physiology with ⁇ 7.4: ⁇ a pharmaceutically acceptable carrier such as water.
  • This solution can be introduced into the patient's intramuscular blood stream by local bolus injection.
  • the daily dose will generally vary depending on the age, weight, and individual patient responsiveness, and the severity of the patient's symptoms. It will ultimately be determined by the attending physician.
  • the receptor is Fas
  • the corresponding compound is administered to a human patient who is being treated for cancer.
  • To about 2 OmgZk preferably from 0.05 mgZkg to about 1 OmgZkggJ ⁇ per day.
  • the function of the C-terminus of the cell membrane receptor can be analyzed, as will be apparent from Examples 39-44 and 84-85 described below.
  • the cell membrane receptor can be expressed in a cell or tissue in which the ligand of the receptor or its agonist is used in combination.
  • Receptors also include those having the tSXX motif described above, which can be targeted to all cell membrane receptors.
  • an effective amount of an anti-Fas antibody or Fas ligand and a compound of the present invention, such as Ph-NHCO-SLV-OEt is effective for cancer cells having the receptor but not causing apoptosis.
  • the receptor is a VIP receptor
  • an effective amount of VIP is used in combination with a compound of the present invention, for example, Ph—NHCO—SLV—OEt
  • the VIP signal is suppressed
  • the RCR region of the VIP receptor worked for signal induction.
  • ⁇ 2 adrenergic receptor and IL-18 receptor
  • the C-terminal region of the receptor is involved in signal ⁇ in the compound of the present invention. It was also clarified whether the RCR region is acting suppressively or inducibly on the signal of the receptor.
  • the compound of the present invention is extremely useful in a method for analyzing the function of the C-terminus of a cell membrane receptor.
  • the present invention includes a method for regulating the signal of a fine sai receptor by inhibiting the binding between the C-terminus of a cell membrane receptor and its binding protein.
  • the present invention is also applicable to the treatment of diseases caused by abnormal cell membrane receptor signals or diseases related to cell membrane receptor signal transduction even if the abnormal signal is not a direct cause.
  • the receptor is F s, as in ⁇ 3 ⁇ 4, the signal from F a s with respect to cell death can be positively regulated by inhibiting the binding of F s and PTP-B AS. Therefore, the method of modulating the signal from F as in this way is applicable to the treatment of cancer.
  • Abnormality of the Fas signal has been strongly proven to cause autoimmune diseases (Nagata, S. and P. Golstein (1995), "The Fas death factor", Science (Wash. DC), 267: 1449-1456) Therefore, the above method can be a treatment method for immunological / allergic diseases.
  • the inhibition of binding as shown in Examples 31, 38, 39, 40, and 84 below, the ability to use a derivative of the C-terminal peptide SLV of Fas is limited to this. is not.
  • Examples 41 and 44 indicate that the presence of a protein binding to the C-terminus of the VIP receptor ⁇
  • the signal from the VIP receptor can be negatively regulated with respect to the action of VIP.
  • VIP antagonists suppress the growth of non-small cell lung cancer
  • methods that negatively regulate the signal from the VIP receptor can be applied to the treatment of lung cancer.
  • a derivative of the C-terminal peptide SLV of the VIP receptor can be used to inhibit the binding, but is not limited thereto.
  • the expression of the VIP receptor is found in the lungs as well, the applicable range of the therapy by modulating signal transmission is not limited to lung cancer.
  • Proteins that bind to ⁇ 2 -drainage receptor and IL-18 receptor also bind to each other because their peptide derivatives having a part of the C-terminal sequence regulate their signals in a sequence-dependent manner. It is thought that there is a presence. Cowpea Te, receptor / 9 2 - For ⁇ drain Nadic receptor and IL one 8 receptor, can modulate signal by inhibiting with these, the binding of their C-terminal binding protein is unidentified It is easy to it * that such a modulating method would be effective in treating diseases caused by abnormalities of the signal fe.
  • the receptor targeted by the present invention refers to a cell membrane receptor in general, and is not limited to the receptors mentioned in the above examples.
  • Fmo c Starting from Wang resin with L-valine (400 mg, 0.2 mmol equivalent), Fmo c group (fluorenylmethyloxycarbonyl group) is deprotected, and then Fmo c— Coupling reaction with L-bit isine (0.5M solution) was performed on the solid phase. Deprotection of Fmo c group requires 20% piperidine (DMF solution) The coupling reaction was carried out using DIC (diisopropylcarposimid) and HBTu (0-benzotriazole-1-yl-N, N, ⁇ ', ⁇ '-tetramethylperonium hexafluorophosphate). .
  • the Fmoc group located at the N-terminus of the peptide synthesized on the solid phase was deprotected with piperidine using Wang resin (400 mg) as in Example 1, and the same coupling reaction was performed using benzoic acid.
  • the resulting mixture was further treated with TFA to obtain 32.2 mg of N-benzoyl-L-seryl-L-l-isyl-L-valine (Ph-CO-SLV).
  • Example 5 15.3 mg of N-phenylaminocarbonyl-L-seryl-L-leucyl-L-valine (Ph-NHC0-SLV) obtained in Example 5 was treated with diazomethane in the same manner as in Example 7 to give 8. 2 mg of N-phenylaminocarbyl-L-seryl-L-l-isyl-L-valine methyl ester (Ph-NHC0-SLV-OMe) was obtained.
  • Example 6 15 mg of N-cyclohexylaminocarboxy-L-seryl-L-leucyl-L-valine (Cyh-NHCO-SLV) obtained in Example 6 was treated with diazomethane in the same manner as in Example 7; 8 nig of N-cyclohexylaminocarboxy-L-Ceryl-L L-one-isyl-L-valine methyl ester (Cyh-NHC0-SLV-OMe) was obtained.
  • N— [4-methyl-2 (S) — (N-acetyl-L-seryl) amino-penten-1-yl] 1-L-valine methyl ester is dissolved in 1. Oml of methanol, then 4 equivalents of lithium hydroxide An aqueous solution (0.5 ml) was added, and the mixture was stirred at room temperature for 12 hours under an atmosphere of argon. After neutralizing the reaction mixture, the desired N- [4-methyl-2 (S)-(N-acetyl-l-seryl) amino-pentol-l-yl] -l-valine (Ac 5.4 mg of -SL— 0— (CH 2 NH) —V) was obtained.
  • a peptide was synthesized on Wang resin (400 mg) using Fmoc-N-methyl-0-benzyl-L-serine in place of Fmoc-0-t-l-butyl-L-serine of Example 1.
  • Fmoc-N-methyl-0-benzyl-L-serine in place of Fmoc-0-t-l-butyl-L-serine of Example 1.
  • 90.7 mg of N-acetyl-N-methyl-0-benzyl-L-seryl-L-leucyl-L-valine was obtained.
  • 26.9 mg was dissolved in ethanol, and the mixture was stirred for 2.5 hours under a hydrogen atmosphere using palladium hydroxide as a catalyst.
  • a peptide was synthesized on Wang resin (400 mg) using Fmoc-L-phenylalanine instead of Fmoc-L-one-isocyanate of Example 1, and treated in the same manner as in Example 2. 3 mg of N-acetyl-L-seryl-L-phenylalan-L-valine (Ac-S FV) was obtained.
  • the peptide was synthesized on the solid phase using W ng resin (18 Omg) with Fmoc-L-isoleucine, and then treated in the same manner as in Example 2.
  • the reaction solution was separated between ethyl acetate and water, and the obtained organic layer was washed with saturated saline and saturated aqueous sodium hydrogen carbonate, dried with magius, and then dried under reduced pressure.
  • the dried product was dissolved in a mixture of TFA (6 ml) and water (0.3 ml), reacted at room temperature for 40 minutes, and TFA was removed by concentration.
  • the reaction product is separated with ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer is saturated with sodium chloride.
  • the extract was washed with water, dried over sodium sulfate, and concentrated to obtain 0-benzyl-L-seryl-L-loycil-L-valineethyl ester (3.08 g).
  • N-acetyl-0-benzyl-L-seryl-L-leucyl-L-valleethyl ester (0.33 g) was dissolved in methanol (10 ml), and palladium hydroxide-carbon was changed to) ⁇ at room temperature under a hydrogen atmosphere. An hourly catalytic reduction was performed. After removing ⁇ ), the mixture was concentrated to dryness to obtain 215 mg of N-acetyl-L-seryl-L-mouth isyl-L-valinethyl ester (Ac-SLV-OEt).
  • N-phenylaminocarbonyl 0-.benzyl-L-seryl-L-leucyl-L-valinethyl ester 35 mg was dissolved in a mixed solvent of ethanol (10 ml) and DMF (10 ml).
  • H3 ⁇ 4 Catalytic reduction was carried out in the same manner as in Example 22 to obtain 249 mg of the target N-phenylaminocarbonyl L-seryl-L-l-isyl-L-valinethyl ester (Ph-NHCO-SLV-OEt).
  • reaction solution was separated between ethyl acetate and water, and the obtained solution was washed with saturated saline and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and dried under reduced pressure. Dried ⁇ ⁇ 20% Pyridine-DMF solution
  • N-acetyl-0-t-butyl-L-seryl-l-l-isyl-L-alaninetyl ester 13 Omg is dissolved in TFA (2 ml), water (0.1 ml) is added, and the mixture is added at room temperature for 45 minutes. Stirred. The resulting organic layer was washed with saturated sodium bicarbonate solution and saturated: ⁇ water, and then dried over sodium sulfate. The solid obtained by concentrating to dryness is washed with ether Z hexane, and 25 mg of the desired product, N-acetyl-L-seryl mono-L-mouth isyl-L-alanineethyl ester (Ac—SLA—OEt) is obtained. Obtained.
  • Example 22 The 0-t-butyl-L-seryl-L-l-isyl-L-alanineethyl ester (0.4 g) obtained in Example 22 was dissolved in DMF (5 ml), and phenylisocyanate (0.15 ml) was dissolved in DMF (5 ml). In addition, the reaction was carried out at room temperature for 80 minutes. Same as Example 23 In the same manner, 396 mg of N-phenylaminocarbonyl 0-t-butyl-L-seryl-L one-port isyl-L-alaninetyl ester was obtained.
  • N-phenylaminocarboxy-L-seryl-L-leucyl-L-one-port isine (Ph-NHC0-SLL) was dissolved in 1.0 ml of ethanolic hydrochloric acid solution, and the solution was dissolved at room temperature. Stirred for 5 hours. After neutralizing the reaction solution, the reaction solution was separated with water and ethyl acetate, and the obtained organic layer was dried over sodium sulfate and concentrated with BE.
  • MRNA of each cell was prepared using Prep Micro mRNA Purification Kit (Pharmacia Biotech).
  • cDNA was prepared from this mRNA by the RT-PCR method using the Superscript Preampliiication System for First Strand cDNA Synthesis (Life Technologies). The expression of PTP-BAS was examined by PCR using this cDNA.
  • cDNA 4/1 prepared from 12.5 ng /; [0.78 ng ⁇ 1 from l was converted to a PTP-BAS-specific primer (5, primer: 5′-GAATACGAGTGTCAGACATGG-3 ′, 3 ′ primer) : 5'-AGGTCTGCAGAGAAGCAAGAATAC-3 ') PCR reaction solution containing 10 M (Recombinant Taq DNA Polymerase, TaKaEa Taq, Takara Shuzo) was added to 21 // 1, and PCR was carried out for 35 cycles.
  • the PCR reaction product 251 was electrophoresed in agarose gel (2%) containing ethidium bromide (0.3 / gZml) and photographed under UV irradiation. It was determined that PTP-BAS was expressed in cells in which a 607 bp PCR reaction product with the PTP-BAS primer was confirmed. As shown in the table, the expression ability of PTP-BAS was observed in 5 out of 8 strains. 7
  • the fusion protein of Gluta thione S—trans ferase and Fa s is a gene encoding amino acids 191-1335 of Fa s (Ito et al., 1991, supra) in vector pGEX-2T (Pharmacia). And were prepared by expressing in a W bacterium.
  • the GST-Fas fusion protein immobilized on the solid phase is obtained by combining the GST-Fas (amino acids 191-335) fusion protein expressed in Escherichia coli with G1 utathione.
  • PTP-BAS fragment 1 is the same as PTP— BAS fragment 1 ⁇ TNT Reti cu lo cy te
  • GST-Fas (2-6 / ⁇ M) immobilized in Benz amidine, 7 ⁇ s / m1Pepstatin) 50 1 or GST-Fas (2-6 uM) not immobilized , the test substance, and [3 5 S] PTP- the BAS fragment 1 were mixed, and 12-16 hours incubation at 4.
  • GST-Fas immobilized G 1 utathi 0 ne
  • 100 HT-29 cells or DLD-l cells are cultured in 100 1 culture medium (1 to 1 ⁇ 1 1640 medium containing 10% to 5 In water for 24 hours at 37 ° C under 5% CO 2, and then add anti-Fas antibody (CH-11, MBL) or culture solution (control) to 101 and 1 OmM at each concentration.
  • Inhibitor of prepared Fas and PTP-BAS Ph—NHCO—SLV—OMe only ImM
  • control 101 was added, and the cells were further cultured for 20 hours.
  • the adhered cells were washed several times with phosphate buffered saline, and the above culture solution 90 ⁇ 1 and ⁇ solution (Chemicon International Co., Ltd.) 10 // 1 were added thereto, followed by culturing for 4 hours. After addition of 100/1 isopropanol containing 0.04% HC1, the absorbance at 570 nm was measured with a microplate reader. The absorbance when cultured in the presence of CH-11 relative to the absorbance of the control (when cultured in the absence of CH-11) was determined and expressed as a percentage.
  • ZPTP-BAS binding inhibition was determined.
  • the blank value was the value when GST-Fas (amino acids 191-320), which is strongly known not to bind to PTP-BAS, was used. Human as negative control
  • FIG. 1 shows the in vitro inhibition of the binding of F asp / PTP-BAS by the C-terminal 15 amino acid peptide of F asp. It shows that the inhibitory activity is higher as the band density of the autoradiograph becomes thinner.
  • the C-terminal 15 amino acid peptide of Fa s (Ac-DSENSNFRNE I QSLV) inhibited the F a s ZP T P—B A S binding in the in vitro manner. Shaded hPAMP did not inhibit the binding of F az ZPTP-BAS at all even in ImM.
  • the ZPTP-BAS binding inhibitory activity was determined.
  • FIG. 2 shows the effect of the C-terminal peptides of Fas of different lengths on the binding of F aZZPTP-BAS.
  • the Fas / PTP-BAS binding inhibitory activity of the 15 to 6 amino acid chain length peptides was comparable. 5 to 3 amino The acid peptide had a weaker Fas / PTP-BAS binding inhibitory activity than the 15-6 amino acid peptide at 10, 100 / M.
  • Two amino acids and one amino acid peptide hardly inhibited FastZPTP-BAS binding.
  • each amino acid of Ac-SLV was replaced with another L-amino acid, and the in vitro Fas / PTP-BAS binding inhibitory activity of the scanned tripeptide was examined.
  • FIG. 3 shows the inhibition of Fa sZP TP-BAS binding in the presence of 1 mM peptide
  • Fig. 4 in the presence of 0.1 mM peptide
  • FIG. 5 shows concentration-dependent curves of inhibition of Fa sZP TP-BAS binding of Ac—SLV and Ac—TLV.
  • ⁇ exhibited the same strong inhibitory activity as s in the presence of the peptide of ImM scanned against S.
  • FIG. 3 center
  • the position of L showed a strong inhibitory activity similar to that of L even when almost all amino acids were substituted in the presence of the ImM peptide.
  • FIG. 3 center
  • the S position of Ac-SLV is S or T
  • the L position is L amino acid or glycine, especially L or
  • the V position is V or I force, respectively.
  • Fig. 6 shows the in vitro binding inhibitory activities of the D-form, N-methyl form and reduced form. These experiments were performed in the presence of the ImM peptide. The substitution of (D) S for each of the eight amino acids retained the inhibitory activity, albeit weaker. The N-methyl form and the reduced form also exhibited lower inhibitory activity than Ac-SLV, but retained the activity.
  • Example 32 the N-terminal modification of Ac—SLV was examined for its in vitro F a s / PTP-BAS binding inhibitory activity.
  • FIG. 7 shows the in vitro binding inhibitory activity by N-terminal modification.
  • the N-terminal modifications are acetyl, open triangles are phenyl peridode, open triangles are cyclohexyl peridode, and open squares are unmodified.
  • the N-terminal modification of SLV increased the binding inhibition activity of in vitro. The order was phenylureido> cyclohexylureido> acetyl.
  • Example 32 According to the method of Example 32, the in vitro F a sZPTP-BAS binding inhibitory activity of the modified C-terminal was examined. The results are shown in FIG.
  • Example 31 the cell death-inducing effect of the FasZPTP-BAS binding inhibitor on human ⁇ cancer DLD-1 was examined.
  • the pre-incubation time was 72 hours, and the degree of inhibition of FasZPTP-BAS binding was from 2.5 mM to 1 OmM.
  • the frequency at 570 nm was measured using a microplate reader, and the value was used as an index of the number of viable cells.
  • Cyh-NHCO-SLV-OMe, Cyh-NHCO-SLV-OEt, Ph-NHCO-SLV-OMe, Ph-NHCO-SLV -OEt was shown to increase the sensitivity of cancer cells to anti-Fas antibodies and induce cell death in cancer cells.
  • Example 31 the cell death-inducing effect of Ph-NHCO-SLV-OEt on human ⁇ cancer DLD-1 was examined. However, the preculture time was 72 hours. The concentration of Ph-NHCO-SLV-OEt to be added was 2.5 mM. Anti-Fas antibody (CH-11) or culture medium and Ph-NHCO-SLV-OEt or a solvent thereof were added, and after 20 hours, photographed under an inverted microscope.
  • Ph-NHCO-SLV-OEt induced significant cell death (apoptosis) in DLD-1 in the presence of CH-11.
  • VIP was administered in a cumulative manner.
  • Drugs such as Ph—NHCO—SLV—OEt were administered VIP in their presence after 15 minutes of pretreatment. The interval between the experiments was 5 minutes, during which the cells were washed 2-3 times with a Tyrode-Hepes solution.
  • VI P showed the maximal response at 3X10_ 6 concentration-dependently relaxed than the tracheal smooth muscle 10 _8 M.
  • the C-terminal sequence one S- L one V human VI P receptors is downy peptide derivatives synthesized based Ph- NHCO- SLV- OE t 1 relaxation reaction of tracheal smooth muscle according to the VIP X 1 ( ⁇ 7 ⁇ It suppressed depending on the concentration in the range of 1 X 10- 4 ⁇ , showed a significant inhibitory effect with 1X10 _5 Micromax more.
  • SLL derivative suppresses isoproterenol-induced bronchoconstriction
  • One address is synthesized based on C-terminal sequence one SLL of nadic receptor was located in the base peptide derivatives Ph- NHCO- SLL-OE t 1 relaxation reaction of tracheal smooth muscle according to I s 0 is XI 0- 7 M ⁇ 1 X 10 _4 M range suppressed depending on the concentration in the showed significant inhibitory effect in 1 X 10 _5 M or more.
  • Ph—NHCO— SLV— OE t was slightly inhibited relaxation response by VIP at a concentration of 1 XI (T 7 M ⁇ 1 XI 0 _4 M.
  • a cell line which highly expresses human IL-8 receptor was established. Specifically, cDNA of hIL-8B receptor (hIL-8BR) was introduced into HEK293 cells using pEFneo to obtain cells stably and highly expressing hIL-8BR. This has cells were large increase in h IL one 8 When the adapted intracellular C a 2+, pEFn eo cells transfected with only h IL poles also intracellular C a 2+ by adding an 8 There was only a slight rise.
  • hIL-8B receptor cDNA of hIL-8B receptor
  • the cells were then cultured in 260 ml flasks in DMEM, 10% FCS, 1% penicillin-streptomycin (GIBC0-BRL), G418 600 / g / ml. When it became onf 1 uent, it was used for the experiment. After aspirating the medium, the medium was washed with 5 ml of PBS and incubated with 5 # 1 ⁇ Fura 2-AM (HEP ES buffer) for 30 minutes. After washing with 5 ml of PBS and trypsin treatment, 8.5 ml of HE PES buffer was added, and the mixture was centrifuged (100 rpm x 3 min) to remove the supernatant.
  • DMEM fetal bovine serum
  • JASCO Corporation CAF-100 was used for the measurement of intracellular Ca 2+ .
  • Lml of the cell suspension prepared above was placed in a cuvette containing a small stirrer bar, and the solution was kept at 37 ° C while stirring to measure.
  • the solution was kept at 37 ° C while stirring to measure.
  • NHCO-TTL-OEt inhibited the uptake of intracellular Ca2 + by IL-18 of human IL-8B receptor gene transfectant.
  • Example 41 Using the rat bronchus instead of the bronchus of the guinea pig, the inhibitory effect of the compound on VIP-induced bronchial relaxation was measured in the same manner as in Example 41. After pretreatment with Ph-NHCO-SLV-OEt for 15 minutes, VIP was administered in its presence. The interval between experiments was 5 minutes, and the cells were washed 2-3 times with the Tyrode-Hepes solution.
  • P is a base peptide derivatives were synthesized based on the C-terminal sequence one SL one V rat VIP receptacle descriptor one h- NHCO- SLV- OE t is the relaxation response of rat tracheal smooth muscle according to VIP 1 x 1 (6 ⁇ It was significantly suppressed in the range of 1X10 _4 ⁇ .
  • N— (4-aminophenyl) Aminocarbon L-L-Ceryl-1 L instead of the L Barin ((4 one NH 2) P h-NHCO- S LV) of Example 45 of 2 two Torofue two Ruisoshiane Bok, using 4 twelve trough E sulfonyl iso Xia sulfonates, similarly processed It was obtained the objective N-(4 one Aminofue sulfonyl) Aminokarubo two Lou L- Seriru L- mouth Ishiru L one-valine ((4 one NH 2) Ph-NHCO-SLV )) by.
  • N- (2-Aminophenyl) aminocarboyl obtained in Example 45 0-t 1-butyl-L-seryl-1 L-one-isyl-L-valine-t-butyl ester and N-Boc-L-glutamic acid 1-t-butyl
  • the ester was condensed in the same manner as in Example 22 and treated with TFA to give the desired N- (2- (L-glutamylamino) phenyl) aminocarbonyl-1-L-seryl-L-mouth isyl-L-valine (2- (G 1 u-NH) Ph-NHCO-SLV) was obtained.
  • N- (4-Aminophenyl) aminocarbo-2-ol 0-t-butyl-L-seryl-L-mouth isyl-L-valine-t-butylester obtained as an intermediate in Example 47 was treated in the same manner as in Example 48.
  • the desired N- (4- (L-glutamylamino) phenyl) aminocarbone-L-seryl-L-l-isyl-L-parin (4- (G1u-NH) Ph-NHCO-SLV) was obtained.
  • the objective is obtained by treating in a similar manner using N-Ac-L-glutamic acid-t-butyl ester in place of the N-Boc-L-glutamic acid 17-t-butyl ester of Example 48.
  • N- (2- (N-acetyl-L-glutamylamino) phenyl) aminocarbone-L-seryl-L-mouth isyl-L-valine (2- (AcG1u-NH) Ph-NHCO-SLV) was.
  • N-Ac-L-glutamic acid-7-t-butyl ester was used instead of N-Boc-L-glutamic acid-7-t-butyl ester.
  • N- (3- (N-acetyl-L-daltamylamino) phenyl) aminocarbone-L-seryl-L-mouth isyl-L-valine (3- (AcG1u-NH) Ph-NHCO-SLV) was obtained.
  • N-Ac-L-dartamic acid-t-butyl ester instead of N-B0c-L-glucamic acid-t-butyl ester of Example 50.
  • N- (3-Aminophenyl) aminocarbo-2-O-t-butyl-L-seryl-L-one-port isyl-L-valine-t-butyl obtained as an intermediate of Example 46
  • the stele and mono-tert-butyl phthalate were condensed in the same manner as in Example 22 and treated with TFA to give the desired N- (3- (2-carboxybenzamide) phenyl) amino.
  • Carbonyl-l-seryl-l-isyl-l-valine (3- (Pht-NH) Ph-NHCO-SLV) was obtained.
  • Example 77 The reaction of Example 77 was carried out except for N- (3- (2-carboxybenzamido) phenyl) aminocarboyl-L-seryl-L-l-isyl-L-valine (3- (Pht-NH) Ph-NHCO-SLV) N- (3_phthalimidophenyl) aminocarboyl L-seryl-L-l-isyl-L-valine ((3-PhN) -Ph-NHCO-SLV) was given as the product. .
  • the binding inhibitory activity of Fas / PTP-BAS was measured.
  • Table 6 shows the inhibitory activity of the modified N-terminus on in vivo binding.
  • Table 6 Inhibition of Fas-PTP-BAS binding in vitro
  • a microgrid cover slip (Serocate, Eppendorf) is fixed in a 35 mm diameter plastic petri dish, and 2 ml of a culture medium (RPI 1640 medium containing 10% FCS, Nissui Pharmaceutical) is used in the Petri dish.
  • RPI 1640 medium containing 10% FCS, Nissui Pharmaceutical a culture medium containing 10% FCS, Nissui Pharmaceutical
  • CH-11 anti-Fas antibody treated cells
  • 500 ng / ml CH-11 was added to the Petri dish immediately before microinjection.
  • Nuclei were stained with PBS containing l% Hoechst 33342 16-20 hours after microinjection and photographed.
  • FITC FITC-labeled Cells stained with FITC
  • cells that had undergone apoptosis due to morphological changes in the nucleus by phase contrast microscopic fiber images and Hoechst 33342 staining were determined, and the number of cells was counted.
  • the compound of the present invention for the migration of human neutrophils by IL-18 (Ph-NHCO-
  • the effect of TTL-OE t) was evaluated by counting neutrophils that had migrated to the lower chamber using a chemotaxis chamber.
  • the filter of Chemotaxis stir bar used was one manufactured by Neuro probe (pore size 3 / ⁇ m).
  • RPMI medium containing 0.1% BSA was used for neutrophil, IL-18, sample dilution, etc. Add 10 -8 M IL-18 to the lower chamber, and neutrophil suspension 100 ⁇ 1 to the upper chamber
  • the compound of the present invention Since the compound of the present invention has an activity of regulating the function of cell membrane receptor, it can be used for treating ⁇ involved in signal transduction of cell membrane receptor.

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Abstract

Nouveaux peptides dont l'activité consiste à réguler la fonction d'un récepteur membranaire cellulaire portant une séquence d'acides aminés intra-cellulaire carboxy-terminale de -A1-A2-A3, portant une séquence d'acides aminés constituée d'au moins trois acides aminés dans le sens de la longueur, et présentant une séquence carboxy-terminale de -X-Y-Z (dans laquelle X est identique à A1 ou représente un acide aminé appartenant à la même catégorie que A1; Y représente un L-amino acide ou la glycine; et Z est identique à A3 ou représente un acide aminé appartenant à la même catégorie que A3); leurs dérivés présentant une meilleure stabilité biologique, une meilleure perméabilité de membrane cellulaire ou l'activité régulatrice précitée et leur sels pharmaceutiquement acceptables. L'invention concerne également des compositions médicinales contenant ces composés; un procédé d'analyse de la fonction d'un récepteur ou de sa partie C-terminale à l'aide de ces composés; un procédé de régulation de la transmission du signal par un récepteur membranaire cellulaire; et un procédé de traitement de maladies associées à la transmission de signaux par des récepteurs membranaires cellulaires.
PCT/JP1996/002697 1995-09-19 1996-09-19 Nouveaux composes peptidiques et leurs compositions medicinales WO1997011091A1 (fr)

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US6743630B2 (en) 2002-03-06 2004-06-01 The Trustees Of Columbia University In The City Of New York Method of preparing a protein array based on biochemical protein-protein interaction
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US7541151B2 (en) 1997-06-05 2009-06-02 Duke University Single-cell biosensor for the measurement of GPCR ligands in a test sample
US7572888B2 (en) 1997-06-05 2009-08-11 Duke University Methods of assaying receptor activity and constructs useful in such methods
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US10100087B2 (en) 2012-01-13 2018-10-16 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6911526B2 (en) 1996-07-22 2005-06-28 The Trustees Of Columbia University In The City Of New York Compounds that inhibit the interaction between signal-transducing proteins and the GLGF (PDZ/DHR) domain and uses thereof
EP0935467A4 (fr) * 1996-07-22 2002-07-03 Univ Columbia Composes inhibiteurs de l'interaction entre proteines transductrices de signaux et le domaine glgf (pdz/dhr), et utilisation de tels composes
US7572888B2 (en) 1997-06-05 2009-08-11 Duke University Methods of assaying receptor activity and constructs useful in such methods
EP1441032A1 (fr) 1997-06-05 2004-07-28 Duke University Procédés d'analyse de l'activité de récepteurs et produits de recombinaison utiles dans de tels procédés
US7138240B2 (en) 1997-06-05 2006-11-21 Duke University Methods of assaying receptor activity
US7541151B2 (en) 1997-06-05 2009-06-02 Duke University Single-cell biosensor for the measurement of GPCR ligands in a test sample
US6743630B2 (en) 2002-03-06 2004-06-01 The Trustees Of Columbia University In The City Of New York Method of preparing a protein array based on biochemical protein-protein interaction
US10221224B2 (en) 2005-10-17 2019-03-05 Memorial Sloan Kettering Cancer Center WT1 HLA class II-binding peptides and compositions and methods comprising same
US11548924B2 (en) 2005-10-17 2023-01-10 Memorial Sloan Kettering Cancer Center WT1 HLA class II-binding peptides and compositions and methods comprising same
US11414457B2 (en) 2006-04-10 2022-08-16 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof
US10100087B2 (en) 2012-01-13 2018-10-16 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof
US10815274B2 (en) 2012-01-13 2020-10-27 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof
US9919037B2 (en) 2013-01-15 2018-03-20 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof
US10815273B2 (en) 2013-01-15 2020-10-27 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof
US11859015B2 (en) 2013-01-15 2024-01-02 Memorial Sloan Kettering Cancer Center Immunogenic WT-1 peptides and methods of use thereof

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