CN107137409A - A kind of CDK4/6 inhibitor combines the purposes in the medicine for preparing treatment breast cancer with estrogen receptor antagon - Google Patents
A kind of CDK4/6 inhibitor combines the purposes in the medicine for preparing treatment breast cancer with estrogen receptor antagon Download PDFInfo
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- CN107137409A CN107137409A CN201710110542.8A CN201710110542A CN107137409A CN 107137409 A CN107137409 A CN 107137409A CN 201710110542 A CN201710110542 A CN 201710110542A CN 107137409 A CN107137409 A CN 107137409A
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- SGJLSPUSUBJWHO-UHFFFAOYSA-N CC(C1=C(C)c2cnc(Nc3ncc(C4CCNCC4)cc3)nc2N(C2CCCC2)C1=O)=O Chemical compound CC(C1=C(C)c2cnc(Nc3ncc(C4CCNCC4)cc3)nc2N(C2CCCC2)C1=O)=O SGJLSPUSUBJWHO-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
Combine the purposes in the medicine for preparing treatment breast cancer with estrogen receptor antagon the present invention relates to a kind of CDK4/6 inhibitor.Specifically, CDK4/6 inhibitor of the present invention is compound A or its officinal salt, and estrogen receptor antagon is one or more of in Tamoxifen, fulvestrant.
Description
Technical field
Combine the present invention relates to a kind of CDK4/6 inhibitor with estrogen receptor antagon and preparing the medicine for the treatment of breast cancer
Purposes in thing.
Background technology
Breast cancer is one of most common malignant tumour of women, high with the incidence of disease, has much invasion, but course advancement is slow
Slowly, Chinese population association 2010 year 2 month issues in Beijing on the 1st《Chinese mammary gland disease survey report》, report display, China city
The death rate of city area breast cancer increases 38.91%, and breast cancer, which has become, threatens WomanHealth maximum disease, at present
In at least 156 kinds of breast cancer medicines for grinding and listing, wherein 68% is target therapeutic agent.Numerous studies find tumour and thin
Born of the same parents' cycle is extremely related, and the mass mutation of mitogenic signals albumen and antimitotic signal protein defect are led in tumour cell
Cause Proliferative Disorders；Simultaneously all there is genomic instability (GIN) and genome unstability (CIN) in most of tumour, this
Three kinds of basic cell cycle defects are all directly or indirectly caused by the out of control of CDKs.Cyclin dependent kinase (CDK,
Cyclin Dependent Kinase) inhibitor is increasingly becoming popular target.
The a generation two generations CDK inhibitor developed at present is a lot, two generation medicines of greatest concern include Pfizer companies and
The CDK4/6 inhibitor PD-0332991 of Onyx companies joint development, its activity by suppressing CDK4/6 suppresses Rb phosphoric acid
Change, E2F-Rb compounds is detained in endochylema, block the startup of cell cycle.Clinical test results (NCT00721409) show
Show, the progresson free survival phase (Progression-free survival, PFS) of the patient of Letrozole single therapy is 7.5 months,
And the patient of Letrozole and the treatment of PD-0332991 drug combinations then extends to 26.1 months its progresson free survival phase, this is significantly excellent
Gesture obtains extensive concern.Hormone receptor positive metastatic breast cancer for formerly receiving progression of disease after endocrinotherapy
Patient, the combination of PD-0332991 and fulvestrant is alone compared to fulvestrant also to extend its progression free survival phase
(Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer.The new
england journal of medicine.July 16,2015vol.373no.3.)
WO2014183520 discloses a series of CDK4/6 suppressions that meet formula (I) formula similar to PD-0332991 structures
Preparation, inhibitory activity and high selectivity with significant CDK4/6, and these expected compounds are possibly used for a series of swollen
Knurl, and can be used in combination with a series of existing antitumor agents, including formula A compounds as follows, its chemistry
Entitled 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido [2,3-d] is phonetic
Pyridine -7 (8H) -one：
But above-mentioned document does not have and specifically discloses when which compound is combined with any antitumor agent and can obtain
Preferable effect, more it is not anticipated that some specific combination modes can obtain synergy.
The content of the invention
The present invention is it has surprisingly been found that compound A or its officinal salt are obtained when being used in combination with estrogen receptor antagon
Significant synergy, so as to complete the present invention.
One aspect of the present invention provides compound A or its officinal salt is combined with estrogen receptor antagon in preparation treatment
Purposes in the medicine of breast cancer.Described estrogen receptor antagon can be TAM, fulvestrant, preferably fluorine dimension department
Group.
Wherein described breast cancer is preferably that estrogen receptor positive (ER+), and/or human epidermal growth factor receptor 2 are cloudy
The breast cancer of property (HER2-)；The Locally Advanced or metastatic breast cancer of more preferably above-mentioned phenotype.
In the present invention, compound A is in actual use, preferably the form of its officinal salt, can be various organic acids
Or the addition salts of inorganic acid, wherein particularly preferred isethionate, its structure is as follows：
It is highly preferred that the compound A of present invention isethionate exists in the form of the crystallization of I types, Cu-Ka spokes are used
Penetrate, obtain the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance, the I types crystallization has as shown in Figure 1
X-ray powder diffraction collection, wherein in about 4.17 (21.17), 8.26 (10.69), 9.04 (9.77), 10.78 (8.20),
12.38 (7.14), 14.01 (6.32), 18.50 (4.79), 18.89 (4.70), 20.69 (4.29), 21.58 (4.11), 23.87
And there is characteristic peak 28.15 (3.17) (3.73).
Described I crystal has good stability through being tested under illumination, high temperature and super-humid conditions, and dissolubility, bioavilability
Better than compound A in itself.
In the present invention, every consumption per day (in terms of compound A) scope of compound A or its officinal salt can be 0.1mg/
Kg~1000mg/kg, preferably 0.5~10mg/kg, more preferably 0.5~5mg/kg.For the adult mankind, preferably with compound A
Meter, per consumption per day 1mg~1000mg, preferably 10~500mg, most preferably 30 to 300mg.
In the present invention, for the adult mankind, each consumption of estrogen receptor antagon is 1~2000mg, preferably 10
~1000mg, more preferably 100~1000mg.
Heretofore described is used in combination, and does not limit compound A or its officinal salt and estrogen receptor antagon
It is administered simultaneously, can also the two successively administration；In addition, in order to which medication is convenient, can also be by compound A and estrogen receptor antagon
Pharmaceutical composition is made.
Brief description of the drawings
Fig. 1：Show the XRD spectrum of the I crystal of compound A isethionate；
Fig. 2：Show the DSC collection of illustrative plates figures of the I crystal of compound A isethionate；
Fig. 3：PD-0332991, compound A are alone or shared with fulvestrant human breast carcinoma MCF-7 nude mouses are subcutaneously moved
Plant the curative effect of knurl；
Fig. 4：PD-0332991, compound A are alone or share the influence to lotus knurl nude mouse body weight with fulvestrant；
Fig. 5：PD-0332991, compound A are alone or shared with fulvestrant human breast carcinoma MCF-7 nude mouses are subcutaneously moved
Plant the curative effect (tumour photo) of knurl.
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
Experiment tester used
1st, DSC is composed
INSTRUMENT MODEL：Mettler Toledo DSC 1Staree System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：40-400℃
2nd, x-ray diffraction pattern
INSTRUMENT MODEL：Bruker D8Focus X-ray powder diffraction instrument
Ray：Monochromatic Cu-K alpha rays (λ=1.5406)
Scan mode：The θ of θ/2, scanning range：2-40°
Voltage：40KV, electric current：40mA
Embodiment 1：6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyridine
And the preparation of [2,3-d] pyrimidine -7 (8H) -one isethionate
Step 1：6- ((6- (1- vinyl butyl ethers base) -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,
3-d] pyrimidine -2-base) amino) -5', 6'- dihydros-[3,4'- bipyridyls] -1'(2'H)-t-butyl formate preparation
Under argon gas protection, by (10g, 29.06mmol) 2- amino -6- (1- fourths oxyethylene group) -8- cyclopenta -5- methyl pyrroles
Pyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one (by WO2014183520 disclose method prepare), cesium carbonate (14.22g,
43.75mmol)、Pd2(dba)3Double diphenylphosphine -9, the 9- dimethyl xanthenes of (2.12g, 2.31mmol), 4,5- (2.69g,
4.69mmol) put into 125.00g dioxane in three mouthfuls of reaction bulbs, backflow is heated to after stirring, raw material is slowly added dropwise
4- (6- chloropyridine -3- bases) -5,6- dihydropyridines -1 (2H)-carboxylic acid tert-butyl ester (10.34g, 35.00mmol, it is auspicious purchased from Yancheng City
Health medication chemistry Co., Ltd) and dioxane (65.62g, 0.74mol) mixed liquor (time for adding about 5h).Drip Bi Jixu
Return stirring reacts 1~1.5h, and TLC monitoring raw material 2- amino -6- (1- fourths oxyethylene group) -8- cyclopenta -5- picolines are simultaneously
[2,3-d] pyrimidine -7 (8H) -one reaction (solvent completely：Petroleum ether：Ethyl acetate=2:1, raw material Rf=0.6, product Rf=
0.7), terminating reaction.Reaction solution is cooled to room temperature, and filtering, filter cake is washed with dichloromethane 17.19g × 3.By filtrate in 65 DEG C
It is concentrated under reduced pressure dry.Residue adds the dissolving of 137.50g dichloromethane, adds 56.25g purified waters, and point liquid, aqueous phase uses 68.75g again
Dichloromethane is extracted.Merge organic phase, anhydrous sodium sulfate drying, filtering, filter cake is washed with 23.44g dichloromethane, and filtrate is in 45 DEG C
It is concentrated under reduced pressure into oily liquids.150g acetone solutions are added, about 2h, ice-water bath stir about 3h is stirred at room temperature.Filtering, filter cake is with cold
Acetone 25g × 4 are washed, and 8~10h of reduced pressure at room temperature obtains solid about 14.84g, yield：80~92%, HPLC detection purity are not
Less than 90%.ESI/MS:[M+H]=601.43.
Step 2：(((6- acetyl group -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,3-d] are phonetic by 6- by 4-
Pyridine -2- bases) amino) pyridin-3-yl) and piperidines -1- t-butyl formates preparation
By 6- ((6- (1- vinyl butyl ethers base) -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,3-d]
Pyrimidine -2-base) amino) -5', 6'- dihydros-[3,4'- bipyridyl] -1'(2'H)-t-butyl formate (14.84g, 24.69mmol)
Put into 75g acetic acid in three mouthfuls of reaction bulbs, lead to argon gas protection.10%Pd/C (5g) is added, hydrogen is replaced three times, in 50 under stirring
~60 DEG C of atmospheric hydrogenations react 30~32h.HPLC methods monitor intermediate state surplus (6- ((6- (1- vinyl butyl ethers base) -8- rings
Amyl group -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,3-d] pyrimidine -2-base) amino) -5', 6'- dihydros-[3,4'- joins pyrrole
Pyridine] -1'(2'H)-t-butyl formate takes off normal-butyl protection but the intermediate that is not reduced of double bond) ＜ 0.3%, terminating reaction.
Reaction solution is cooled to room temperature, is filtered after the displacement of system argon gas, filter cake is washed with 37.50g dichloromethane.By filtrate in 65 DEG C of decompressions
It is concentrated to dryness.Residue argon gas protection 50g absolute ethyl alcohols backflow mashing 0.5h, naturally cools to room temperature, ice bath is stirred under stirring
Mix about 4h.Filtering, filter cake is washed with cold absolute ethyl alcohol 12.50g × 2.Gained wet product adds dichloromethane 31.25g stirrings, filtering
Insoluble matter, is slowly added to isopropanol 118.75g, ice bath stir about 3h, 8~10h is dried under reduced pressure after filtering to be consolidated under filtrate stirring
Body about 8.75g, yield：60~72%, HPLC detection purity are not less than 98%.ESI/MS:[M+H]=547.26.
Step 3：6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido
The preparation of [2,3-d] pyrimidine -7 (8H) -one isethionate
By 4- (6- ((6- acetyl group -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyrido [2,3-d] pyrimidines -2-
Base) amino) pyridin-3-yl) piperidines -1- t-butyl formates (8.75g, 15.94mmol) and 56.25g absolute methanols put into three mouthfuls
In reaction bulb, stir.80% isethionic acid (8.81g, 55.94mmol) and water 0.94g are dissolved in 13.75g without water beetle
In alcohol, it is added drop-wise in above-mentioned solution, solution becomes clarification.Drop, which finishes, is heated to reflux stirring reaction 3~3.5h, TLC detection raw material reaction
(petroleum ether completely：Ethyl acetate=1:1, raw material Rf=0.3, product Rf=0), terminating reaction is filtered while hot.Under filtrate stirring
Triethylamine (4.00g, 39.38mmol) is added dropwise, Bi Jixu stir about 1h, ice bath stir about 3h is dripped.Filtering, filter cake is with cold without water beetle
Alcohol 7.19g × 2 are washed, and 40 DEG C are dried under reduced pressure 6~8h and obtain solid about 7.97g, yield：82~93%, HPLC detection purity is not low
In 98%.TOF-MS:[M+H]=447.2503 (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -
2- yls) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one combines hydrionic quasi-molecular ions).The X- of the crystallized sample is penetrated
Line diffraction spectrogram is shown in Fig. 1.The crystallization is in about 4.17 (21.17), 8.26 (10.69), 9.04 (9.77), 10.78 (8.20),
12.38 (7.14), 14.01 (6.32), 18.50 (4.79), 18.89 (4.70), 20.69 (4.29), 21.58 (4.11), 23.87
And there is characteristic peak at 28.15 (3.17) places (3.73).DSC spectrograms are shown in Fig. 2, there is melting endothermic peak near 324 DEG C, and this crystal formation is determined
Justice is I crystal.Through testing under illumination, high temperature and super-humid conditions, the crystal formation has good stability.
Embodiment 2：Compound A and PD-0332991 is alone or is shared with fulvestrant to human breast carcinoma MCF-7 nude mouses
The curative effect of subcutaneous transplantation knurl.
1 test medicine
Medicine name：PD-0332991 isethionate is yellow crystalline powder, is disclosed according to CN1835951B
Method prepare；Compound A isethionate is white powder, is prepared by embodiment 1；Fulvestrant is white powder
End, is provided by Hengrui Pharmaceutical Co., Ltd., Shanghai.
Compound method：Compound A isethionate is matched somebody with somebody with 50mM citric acids+0.5%CMC+0.5%Tween 80
System；PD-0332991 isethionate is prepared and diluted with the distilled water containing 0.1%Tween 80；Fulvestrant is with commercially available
Soybean oil is prepared.
2 experimental animals
BALB/cA-nude nude mouses, 6-7 weeks, ♀, purchased from Shanghai Ling Chang bio tech ltd.Production licence
Number：SCXK (Shanghai) 2013-0018；Animal quality certification number 2013001812696.Feeding environment：SPF grades.
3 experimental procedures
(0.72mg/ pieces discharge, Innovative Research of nude mouse subdermal implantation estrogen sustained release tablets for 60 days
America), second day inoculation MCF-7 Human Breast Cancer Cells, treats tumour growth to 100-200mm3Afterwards, animal is grouped at random
(D0).Dosage and dosage regimen are shown in Table 1.2-3 knurl volume is surveyed weekly, claims mouse weight, record data.Gross tumor volume (V) is counted
Calculating formula is：
V=1/2 × a × b2Wherein a, b represent length and width respectively.
T/C (%)=(T-T0)/(C-C0) × 100 wherein T, C are the gross tumor volume at the end of experiment；T0、C0Opened for experiment
The gross tumor volume during beginning.
4 result of the tests
Compound A (75mg/kg, PO, QD 16) significantly inhibits expression ERs human breast carcinoma MCF-7 nude mouse skins
The growth of lower transplantable tumor, tumour inhibiting rate is 130%, there is 8/8 tumor partial regression；Reference agent PD-0332991 same doses and side
Case is 124% to MCF-7 tumour inhibiting rate, there is 7/8 tumor partial regression；Fulvestrant (1mg/, single subcutaneous injection) is right
MCF-7 tumour inhibiting rate is 25%；Compound A, PD-0332991 and fulvestrant share tumour inhibiting rate and significantly improved, respectively from list
148% and 143% (P is brought up to 130% during compound A, PD-0332991 and 124%<0.05, with compound alone A or
PD-0332991 compares).Tumor-bearing mice can be resistant to very well to above medicine, not have the symptoms such as obvious weight loss.Phase
Compare, synergistic effect either alone or to fulvestrant, therapeutic equivalences of the compound A and PD-0332991 to MCF-7.
Claims (10)
1. compound A or its officinal salt combine the use in the medicine for preparing treatment breast cancer with estrogen receptor antagon
On the way,
2. purposes according to claim 1, wherein the estrogen receptor antagon is in Tamoxifen, fulvestrant
One or more, preferably fulvestrant.
3. purposes according to claim 1, wherein described breast cancer is the breast cancer of estrogen receptor positive (ER+).
4. purposes according to claim 1, wherein described breast cancer is that human epidermal growth factor receptor 2 is negative
(HER2-) breast cancer.
5. purposes according to claim 1, wherein described breast cancer is Locally Advanced or metastatic breast cancer.
6. purposes according to claim 1, wherein described compound A officinal salt is isethionate.
7. purposes according to claim 6, wherein described isethionate exists with I types crystal form, uses Cu-
Ka is radiated, and obtains the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance, and the I types crystallization has such as Fig. 1 institutes
The X-ray powder diffraction collection shown, wherein in about 4.17 (21.17), 8.26 (10.69), 9.04 (9.77), 10.78
(8.20), 12.38 (7.14), 14.01 (6.32), 18.50 (4.79), 18.89 (4.70), 20.69 (4.29), 21.58
(4.11), there is characteristic peak 23.87 (3.73) and 28.15 (3.17).
8. every consumption per day of purposes according to claim 1, wherein compound A or its officinal salt (in terms of compound A)
Scope is 0.1mg/kg~1000mg/kg, preferably 0.5~10mg/kg, more preferably 0.5~5mg/kg.
9. every consumption per day 1mg~1000mg of purposes according to claim 1, wherein compound A or its officinal salt, excellent
Select 10~500mg, most preferably 30 to 300mg.
10. purposes according to claim 1, wherein each consumption of the estrogen receptor antagon is 1~2000mg,
It is preferred that 10~1000mg, more preferably 100~1000mg.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN2016101143942 | 2016-03-01 | ||
| CN201610114394 | 2016-03-01 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020156446A1 (en) * | 2019-01-30 | 2020-08-06 | 江苏恒瑞医药股份有限公司 | Use of composition containing cdk4/6 inhibitor in combination with anastrozole in preparation of medicament for treating tumor diseases |
| WO2021110122A1 (en) * | 2019-12-05 | 2021-06-10 | 基石药业（苏州）有限公司 | Combination therapy of cdk4/6 inhibitor |
| WO2022184146A1 (en) * | 2021-03-03 | 2022-09-09 | 正大天晴药业集团股份有限公司 | Combined pharmaceutical composition containing cdk4/6 inhibitor and use thereof |
| WO2023284790A1 (en) * | 2021-07-13 | 2023-01-19 | 江苏恒瑞医药股份有限公司 | Use of selective estrogen receptor covalent antagonist in combination with cdk4/6 inhibitor in the preparation of medicine for treating breast cancer |
| WO2024153229A1 (en) * | 2023-01-19 | 2024-07-25 | 江苏恒瑞医药股份有限公司 | Anti-her2 antibody-drug conjugate for treating breast cancer |
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| CN1835951A (en) * | 2003-07-11 | 2006-09-20 | 沃尼尔·朗伯有限责任公司 | Isethionate salt of a selective CDK4 inhibitor |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020156446A1 (en) * | 2019-01-30 | 2020-08-06 | 江苏恒瑞医药股份有限公司 | Use of composition containing cdk4/6 inhibitor in combination with anastrozole in preparation of medicament for treating tumor diseases |
| CN113395969A (en) * | 2019-01-30 | 2021-09-14 | 江苏恒瑞医药股份有限公司 | Application of CDK4/6 inhibitor-containing composition and anastrozole in preparation of drugs for treating tumor diseases |
| WO2021110122A1 (en) * | 2019-12-05 | 2021-06-10 | 基石药业（苏州）有限公司 | Combination therapy of cdk4/6 inhibitor |
| WO2022184146A1 (en) * | 2021-03-03 | 2022-09-09 | 正大天晴药业集团股份有限公司 | Combined pharmaceutical composition containing cdk4/6 inhibitor and use thereof |
| CN120022281A (en) * | 2021-03-03 | 2025-05-23 | 正大天晴药业集团股份有限公司 | Combination pharmaceutical composition of CDK4/6 inhibitors and use thereof |
| WO2023284790A1 (en) * | 2021-07-13 | 2023-01-19 | 江苏恒瑞医药股份有限公司 | Use of selective estrogen receptor covalent antagonist in combination with cdk4/6 inhibitor in the preparation of medicine for treating breast cancer |
| WO2024153229A1 (en) * | 2023-01-19 | 2024-07-25 | 江苏恒瑞医药股份有限公司 | Anti-her2 antibody-drug conjugate for treating breast cancer |
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Application publication date: 20170908 |