WO2021210636A1 - 乳がん治療剤 - Google Patents

乳がん治療剤 Download PDF

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Publication number
WO2021210636A1
WO2021210636A1 PCT/JP2021/015546 JP2021015546W WO2021210636A1 WO 2021210636 A1 WO2021210636 A1 WO 2021210636A1 JP 2021015546 W JP2021015546 W JP 2021015546W WO 2021210636 A1 WO2021210636 A1 WO 2021210636A1
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Prior art keywords
breast cancer
therapeutic agent
cdk4
estrogen receptor
agent according
Prior art date
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Ceased
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PCT/JP2021/015546
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English (en)
French (fr)
Japanese (ja)
Inventor
恭子 西端
沙世 福島
河野　智
沙里 宮野
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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Priority to JP2022515429A priority Critical patent/JPWO2021210636A1/ja
Priority to US17/918,829 priority patent/US20230149381A1/en
Priority to EP21787967.5A priority patent/EP4122465A4/en
Priority to BR112022020786A priority patent/BR112022020786A2/pt
Priority to MX2022012934A priority patent/MX2022012934A/es
Priority to AU2021255084A priority patent/AU2021255084B2/en
Priority to KR1020227039422A priority patent/KR20230004595A/ko
Priority to CN202180028460.3A priority patent/CN115397415A/zh
Priority to CA3180128A priority patent/CA3180128A1/en
Publication of WO2021210636A1 publication Critical patent/WO2021210636A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a therapeutic agent for breast cancer containing a monocyclic pyridine derivative having an FGFR inhibitory action or a pharmacologically acceptable salt thereof. More specifically, 5-((2- (4- (1- (2-hydroxyethyl) piperidine-4-yl) benzamide) pyridin-4-yl) oxy) -6- (2-methoxyethoxy) -N -For breast cancer therapeutic agents comprising methyl-1H-indole-1-carboxamide or a pharmacologically acceptable salt thereof.
  • Patent Document 2 It has been reported that the above compounds have a high therapeutic effect on bile duct cancer (Patent Document 2), breast cancer (Patent Document 3) and hepatocellular carcinoma (Patent Document 4). Succinate and maleate are known as pharmacologically acceptable salts of the above compounds (Patent Document 5).
  • Palbociclib, abemaciclib, and the like which are cyclin-dependent kinase 4/6 (CDK4 / 6) inhibitors, are used for the treatment of estrogen receptor-positive and HER2-negative breast cancers (Non-Patent Document 1). Further, estrogen receptor antagonists such as tamoxifen and fulvestrant are used for the treatment of estrogen receptor-positive breast cancer (Non-Patent Document 2).
  • Breast cancer is classified according to the presence or absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 (Human epidermal growth factor receptor Type2; HER2). Is being done.
  • Non-Patent Document 3 it is known that if palbociclib and fulvestrant are continuously administered, tolerance develops and no effect is exhibited (Non-Patent Document 4).
  • Bottcher et al. Acta Oncologica, 2019, 58 (2), 147-153. Howell et al., Journal of Clinical Oncology, 2004, 22 (9), 1605-1613. Seki et al., In vivo, 2019, 33, 2037-2044. Nayar et al., Nature Genetics, 2019, 51, 207-216.
  • An object of the present invention is to provide a therapeutic agent for breast cancer that has developed resistance to administration of a CDK4 / 6 inhibitor and an estrogen receptor antagonist.
  • the present inventors have conducted diligent studies, and as a result, the compound represented by the above formula (I) is resistant to the administration of a CDK4 / 6 inhibitor and an estrogen antagonist against breast cancer.
  • the present invention has been completed by finding that it exhibits a high therapeutic effect.
  • the present invention provides the following [1] to [24].
  • CDK4 / 6 inhibitors and estrogen receptor antagonists including -methoxyethoxy) -N-methyl-1H-indole-1-carboxamide or pharmacologically acceptable salts thereof.
  • a therapeutic agent for breast cancer that has developed resistance.
  • a composition for treating breast cancer which comprises.
  • a composition for treating breast cancer which comprises.
  • the therapeutic agent, composition, therapeutic method, compound or use according to the above, wherein the breast cancer is negative for human epidermal growth factor receptor type 2 (HER2).
  • HER2 human epidermal growth factor receptor type 2
  • the estrogen receptor antagonist is at least one selected from the group consisting of tamoxifen, fulvestrant and mepitiostane.
  • FGFR fibroblast growth factor receptor
  • the compound represented by the formula (I) may exert a tumor volume reduction effect on breast cancer that has developed resistance to the administration of a CDK4 / 6 inhibitor and an estrogen antagonist.
  • the compound represented by the formula (I) according to the present invention or a pharmacologically acceptable salt thereof can be produced by the method described in Patent Document 1.
  • the pharmacologically acceptable salt includes, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • salts with organic acids include acetic acid, succinic acid, fumaric acid, maleic acid, tartrate acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like. And salt can be mentioned.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
  • the preferred pharmacologically acceptable salt is succinate or maleate, and the more preferred salt is succinate.
  • 1.5 succinate is preferable (hereinafter, 1.5 succinate of the compound represented by the formula (I) is referred to as compound A).
  • the breast cancer therapeutic agent of the present invention can be orally administered in the form of solid preparations such as tablets, granules, fine granules, powders and capsules, or liquids, jellies and syrups.
  • the breast cancer therapeutic agent of the present invention may be administered parenterally in the form of an injection, a suppository, an ointment, a poultice, or the like.
  • the breast cancer therapeutic agent of the present invention can be formulated by the method described in the 17th revised Japanese Pharmacopoeia.
  • the dose of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is determined by the degree of symptoms, age, sex, body weight, sensitivity difference, administration method, administration time, administration interval, pharmaceutical preparation. It can be appropriately selected according to the type and the like. Usually, when orally administered to an adult (body weight 60 kg), the daily dose is 0.5 mg to 5 g, preferably 1 mg to 1 g, and more preferably 1 mg to 500 mg. This can be administered in 1 to 3 divided doses daily.
  • cyclin-dependent kinase 4/6 (CDK4 / 6) inhibitors are agents that inhibit the activities of CDK4 and CDK6, which are enzymes that are activated in cancer cells and promote disordered cell division. means.
  • CDK4 / 6 inhibitor Preferable examples of the CDK4 / 6 inhibitor include palbociclib, abemaciclib, ribociclib and the like. Palbociclib is preferred.
  • the dose and method of administration of the CDK4 / 6 inhibitor is, for example, in the case of palbociclib, 125 mg is orally administered once a day to an adult for 3 consecutive weeks, and then the drug is withdrawn for 1 week. With this as one cycle, administration is repeated.
  • the CDK4 / 6 inhibitor is ribociclib
  • the usual adult dosage is 600 mg given orally once daily for 3 consecutive weeks, followed by a 1-week rest period. With this as one cycle, administration is repeated.
  • the usual adult dosage is 150 mg given orally twice daily.
  • the estrogen receptor antagonist means an agent that binds to the estrogen receptor expressed in breast cancer cells. By such a mechanism, the binding between the estrogen receptor and estrogen can be inhibited, and the growth of breast cancer cells can be suppressed.
  • estrogen receptor antagonist examples include tamoxifen, fulvestrant, mepitiostane and the like. Fulvestrant is preferred.
  • the dose and method of administration of the estrogen receptor antagonist is, for example, in the case of fulvestrant, 500 mg is intramuscularly administered once every 4 weeks after the first 2 weeks and 4 weeks.
  • estrogen receptor antagonist is tamoxifen, administer 20-40 mg orally per day.
  • estrogen receptor antagonist When the estrogen receptor antagonist is mepitiostane, 20 mg per day is orally administered in two divided doses.
  • an aromatase inhibitor that inhibits estrogen synthesis may be used instead of the estrogen receptor antagonist.
  • the aromatase inhibitor include anastrozole, letrozole, exemestane and the like.
  • breast cancer means a benign or malignant tumor that develops in the mammary gland (duct, lobules). This includes locally advanced breast cancer, metastatic breast cancer, recurrent breast cancer or unresectable breast cancer.
  • Tolerance means that the effects of these agents diminish or disappear while the breast cancer patient continues to receive the CDK4 / 6 inhibitor and the estrogen receptor antagonist.
  • the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is administered after administration of the CDK4 / 6 inhibitor and the estrogen receptor antagonist
  • CDK4 /. 6 It means that the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is administered alone after developing resistance to the administration of the inhibitor and the estrogen receptor antagonist.
  • Example 1 Growth inhibitory effect of compound A after administration of palbociclib and fulvestrant on tumors derived from human breast cancer patients (OD-BRE-0438) NOD-SCID mice (NOD.CB17-Prkdcscid / J, NOD.CB17-Prkdcscid / J, 5-6 patients in each group) Female, Nippon Charles River Co., Ltd.) was used to evaluate the antitumor effect of compound A after the end of the palbociclib and fulvestrant administration period.
  • OD-BRE-0438 is a tumor derived from an estrogen receptor-positive breast cancer patient established by Oncodesign. The above tumor pieces were transplanted subcutaneously into mice and passaged. The tumor excised from the mouse was cut into pieces of about 4 mm square and transplanted to the subcutaneous part of the right flank of each mouse using Tracal ( ⁇ 3.5 mm).
  • ⁇ -estradiol (Fujifilm Wako Pure Chemical Industries, Ltd.) was prepared in a 1 mg / mL solution with 99.5% ethanol (Fujifilm Wako Pure Chemical Industries, Ltd.). Then, the final concentration was adjusted to 2.5 ⁇ g / mL with sterilized water for water supply. Mice were allowed to ingest this freely from the day of tumor transplantation to the end of the study.
  • Tumor volume (mm 3 ) major axis (mm) x minor axis (mm) x minor axis (mm) / 2
  • parvocyclibuicethionate As the parvocyclibuicethionate (Selleck Chemicals), a commercially available drug substance prepared with a 50 mM sodium lactate buffer (pH 4.0) at a concentration of 10 mg / mL was used. As fulvestrant (trade name: Fesolodex intramuscular injection 250 mg, AstraZeneca Co., Ltd.), a commercially available preparation was used as it was.
  • palbociclib and fulvestrant were started 26 days after tumor transplantation.
  • Palbociclib was orally administered at a dose of 100 mg / kg (10 mL / kg) once daily for 14 days.
  • Fulvestrant was also injected subcutaneously on days 26 and 33 at a dose of 250 mg / kg (5 mL / kg).
  • mice On the 40th day, mice were grouped so that the average tumor volume of each group was almost the same.
  • Compound A was dissolved in purified water to a concentration of 2.5 mg / mL. Mice in each group were orally administered Compound A at a dose of 25 mg / kg (10 mL / kg) or 50 mg / kg (20 mL / kg) once daily for 14 days. The control group was untreated.
  • Tumor volume and body weight of each mouse were measured on days 3, 7, 10 and 14 days after the start of administration of Compound A.
  • the changes in the average tumor volume of each group are shown in Table 1 and FIG.
  • Tumor pieces were transplanted subcutaneously into mice and subcultured.
  • the tumor excised from the mouse was cut into pieces of about 4 mm square and transplanted to the subcutaneous part of the right flank of each mouse using Tracal ( ⁇ 3.5 mm), which was donated to the evaluation of antitumor effect.
  • ⁇ -estradiol (Fujifilm Wako Pure Chemical Industries, Ltd.) was prepared in a 1 mg / mL solution with 99.5% ethanol (Fujifilm Wako Pure Chemical Industries, Ltd.). Then, the final concentration was adjusted to 2.5 ⁇ g / mL with sterilized water for water supply. Mice were allowed to ingest this freely from the day of tumor transplantation to the end of the study.
  • Compound A was dissolved in purified water to a concentration of 2.5 mg / mL. On the 32nd day after tumor transplantation, mice were grouped so that the average tumor volume of each group was almost the same. The tumor volume was calculated by the same method as in Example 1.
  • mice in each group were orally administered compound A at a dose of 50 mg / kg (20 mL / kg) once a day for 14 days.
  • the control group was untreated.
  • Tumor volume and body weight of each mouse were measured on days 3, 7, 10 and 14 days after the start of administration of Compound A.
  • the changes in the average tumor volume of each group are shown in Table 2 and FIG.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP2021/015546 2020-04-17 2021-04-15 乳がん治療剤 Ceased WO2021210636A1 (ja)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2022515429A JPWO2021210636A1 (https=) 2020-04-17 2021-04-15
US17/918,829 US20230149381A1 (en) 2020-04-17 2021-04-15 Breast cancer therapeutic agent
EP21787967.5A EP4122465A4 (en) 2020-04-17 2021-04-15 THERAPEUTIC AGENT AGAINST BREAST CANCER
BR112022020786A BR112022020786A2 (pt) 2020-04-17 2021-04-15 Agente terapêutico de câncer de mama
MX2022012934A MX2022012934A (es) 2020-04-17 2021-04-15 Agente terapeutico para cancer de mama.
AU2021255084A AU2021255084B2 (en) 2020-04-17 2021-04-15 Breast cancer therapeutic agent
KR1020227039422A KR20230004595A (ko) 2020-04-17 2021-04-15 유방암 치료제
CN202180028460.3A CN115397415A (zh) 2020-04-17 2021-04-15 乳腺癌治疗剂
CA3180128A CA3180128A1 (en) 2020-04-17 2021-04-15 Breast cancer therapeutic agent

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JP2020074386 2020-04-17
JP2020-074386 2020-04-17

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US (1) US20230149381A1 (https=)
EP (1) EP4122465A4 (https=)
JP (1) JPWO2021210636A1 (https=)
KR (1) KR20230004595A (https=)
CN (1) CN115397415A (https=)
AU (1) AU2021255084B2 (https=)
BR (1) BR112022020786A2 (https=)
CA (1) CA3180128A1 (https=)
MX (1) MX2022012934A (https=)
WO (1) WO2021210636A1 (https=)

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JPWO2022025150A1 (https=) * 2020-07-31 2022-02-03
US12364690B2 (en) 2015-03-25 2025-07-22 National Cancer Center Therapeutic agent for bile duct cancer
US12414945B2 (en) 2015-12-17 2025-09-16 Eisai R&D Management Co., Ltd. Therapeutic agent for breast cancer

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US20140235614A1 (en) 2013-02-20 2014-08-21 Eisai R&D Management Co., Ltd. Monocyclic pyridine derivative
WO2017104739A1 (ja) * 2015-12-17 2017-06-22 エーザイ・アール・アンド・ディー・マネジメント株式会社 乳がん治療剤
US20170217935A1 (en) 2014-08-18 2017-08-03 Eisai R&D Management Co., Ltd. Salt of monocyclic pyridine derivative and crystal thereof
US20180015079A1 (en) 2015-03-25 2018-01-18 National Cancer Center Therapeutic agent for bile duct cancer
WO2019189241A1 (ja) 2018-03-28 2019-10-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 肝細胞癌治療剤

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US20140235614A1 (en) 2013-02-20 2014-08-21 Eisai R&D Management Co., Ltd. Monocyclic pyridine derivative
US20170217935A1 (en) 2014-08-18 2017-08-03 Eisai R&D Management Co., Ltd. Salt of monocyclic pyridine derivative and crystal thereof
US20180015079A1 (en) 2015-03-25 2018-01-18 National Cancer Center Therapeutic agent for bile duct cancer
WO2017104739A1 (ja) * 2015-12-17 2017-06-22 エーザイ・アール・アンド・ディー・マネジメント株式会社 乳がん治療剤
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WO2019189241A1 (ja) 2018-03-28 2019-10-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 肝細胞癌治療剤

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Title
BOTTCHER ET AL., ACTA ONCOLOGICA, vol. 58, no. 2, 2019, pages 147 - 153
FORMISANO, LUIGI ET AL.: "Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer", NATURE COMMUNICATIONS, vol. 10, no. 1373, 2019, pages 1 - 14, XP055867436, DOI: https://doi.org/10.1038/s41467-019-09068-2 *
HOWELL ET AL., JOURNAL OF CLINICAL ONCOLOGY, vol. 22, no. 9, 2004, pages 1605 - 1613
JAPANESE PHARMACOPOEIA
NAYAR ET AL., NATURE GENETICS, vol. 51, 2019, pages 207 - 216
See also references of EP4122465A4
SEKI ET AL., IN VIVO, vol. 33, 2019, pages 2037 - 2044

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12364690B2 (en) 2015-03-25 2025-07-22 National Cancer Center Therapeutic agent for bile duct cancer
US12414945B2 (en) 2015-12-17 2025-09-16 Eisai R&D Management Co., Ltd. Therapeutic agent for breast cancer
JPWO2022025150A1 (https=) * 2020-07-31 2022-02-03
EP4151212A4 (en) * 2020-07-31 2024-04-10 Eisai R&D Management Co., Ltd. Therapeutic agent for breast cancer
JP7792336B2 (ja) 2020-07-31 2025-12-25 エーザイ・アール・アンド・ディー・マネジメント株式会社 乳がん治療剤

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MX2022012934A (es) 2022-11-08
EP4122465A1 (en) 2023-01-25
US20230149381A1 (en) 2023-05-18
CA3180128A1 (en) 2021-10-21
BR112022020786A2 (pt) 2022-11-29
AU2021255084B2 (en) 2026-04-02
KR20230004595A (ko) 2023-01-06
CN115397415A (zh) 2022-11-25
AU2021255084A1 (en) 2022-12-08
JPWO2021210636A1 (https=) 2021-10-21
EP4122465A4 (en) 2024-03-20

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