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WO2025103341A1 - Combinaison pharmaceutique d'un médicament combiné à un inhibiteur de parp7, et son utilisation dans le traitement de tumeurs - Google Patents

Combinaison pharmaceutique d'un médicament combiné à un inhibiteur de parp7, et son utilisation dans le traitement de tumeurs Download PDF

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Publication number
WO2025103341A1
WO2025103341A1 PCT/CN2024/131698 CN2024131698W WO2025103341A1 WO 2025103341 A1 WO2025103341 A1 WO 2025103341A1 CN 2024131698 W CN2024131698 W CN 2024131698W WO 2025103341 A1 WO2025103341 A1 WO 2025103341A1
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Prior art keywords
alkyl
independently
inhibitor
cancer
parp7
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Chinese (zh)
Inventor
魏用刚
叶飞
陈杨
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Kangbaida Sichuan Biotechnology Co Ltd
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Kangbaida Sichuan Biotechnology Co Ltd
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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present application belongs to the field of medical technology and relates to a drug combination that can be used for anti-tumor. Specifically, the present application relates to a drug combination of a PARP7 inhibitor and its use in treating tumors.
  • TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • PARP7 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly (ADP-ribose) polymerase
  • AHR aryl hydrocarbon receptor
  • PARP7 interacts with the kinase TBK1 and ADP-ribosylates it, resulting in inhibition of TBK1 activity and downregulation of IFN-I (type I interferon) response, which in turn leads to inhibition of the body's antiviral and tumor immune responses.
  • CTLA-4 or cytotoxic T-lymphocyte-associated protein 4 (also called CD152), is a transmembrane protein on the surface of T cells encoded by the CTLA-4 gene.
  • CTLA-4 and CD28 have up to 70% homology, and both bind to the same ligand B7 molecule (CD80 and CD86).
  • CD28 is a co-stimulatory immune checkpoint responsible for transmitting activation signals to T cells, promoting T cell differentiation and proliferation into effector cells; while CTLA-4 is a co-inhibitory immune checkpoint responsible for transmitting inhibitory signals to T cells and inhibiting T cell activity. Due to its higher affinity with the B7 molecule, CTLA-4 competes and blocks CD28's activation of T cells, thereby inhibiting T cell proliferation and activation.
  • CTLA-4 inhibitors block CTLA-4, thereby reactivating T cell differentiation and proliferation into effector cells, infiltrating tumor tissues, and ultimately killing tumor cells.
  • CTLA-4 inhibitors have limited clinical efficacy. Their monotherapy has only shown certain effects in a few tumors such as melanoma, but patients with most tumor types rarely benefit from them.
  • the side effects are large. This is because CTLA-4 inhibitors clear tumor tissue by activating the immune system, which may inevitably lead to over-activation of the immune system and produce immune-related side effects such as diarrhea and rash. Therefore, new improved therapies are urgently needed to enhance the therapeutic effects of existing therapies and reduce side effects.
  • Platinum complexes are cell cycle non-specific drugs and are more broadly classified as alkylating cytotoxic drugs. They mainly interact with DNA in tumor cells to form Pt-DNA adducts, which hinder the normal replication and transcription of DNA. Although different platinum complexes differ slightly in the way and site of binding to DNA, their mechanism of action is essentially the same. Platinum complexes were first discovered as chemotherapy drugs in the 1960s and are one of the most important anticancer drugs in clinical practice. However, platinum complexes represented by cisplatin have severe toxicity, and drug resistance caused by reduced platinum uptake, increased efflux, drug inactivation and DNA damage repair also limits their application. Therefore, new improved therapies are urgently needed to enhance the therapeutic effects of existing therapies, reduce side effects, and overcome drug resistance.
  • PD-1 Programmed death 1 protein
  • Pdcd-1 or CD279 is a 55KD receptor protein related to the CD28/CTLA4 co-stimulatory/inhibitory receptor family.
  • Cancer cells express PD-1's ligand PD-L1, which they use to evade host immune System.
  • the PD-1 inhibitors that are already on the market can significantly prolong the overall survival of patients by interfering with the tumor immunosuppression mechanism.
  • this treatment method can only cause responses in some patients, or some patients may have a good response when they first use the drug, but the efficacy decreases or disappears after a period of use. Therefore, new and improved therapies are urgently needed to enhance the therapeutic effects of existing therapies.
  • the present invention provides a drug combination of a PARP7 inhibitor and its use in treating tumors.
  • One or more embodiments of the present invention provide a drug combination, comprising: a first active ingredient PARP7 inhibitor, a second active ingredient CTLA-4 inhibitor or platinum complex, and optionally a third active ingredient PD-1 inhibitor or PD-L1 inhibitor.
  • the drug combination comprises: (a) a PARP7 inhibitor, (b) a CTLA-4 inhibitor, and optionally (c) a PD-1 inhibitor or a PD-L1 inhibitor.
  • the drug combination comprises: (a) a PARP7 inhibitor, and (b) a CTLA-4 inhibitor.
  • the drug combination comprises: (a) a PARP7 inhibitor, (b) a platinum complex, and optionally (c) a PD-1 inhibitor or a PD-L1 inhibitor.
  • the drug combination comprises: (a) a PARP7 inhibitor, and (b) a platinum complex.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:
  • X2 is O or a single bond
  • X 3 and X 4 are each independently C or N;
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl; or R 1a , R 1b and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl;
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl; or R 2a , R 2b and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl;
  • R 3 is H, D, C 1-6 alkyl, halogen or cyano, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl; or R 4 , R 5 and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl;
  • R 10 is each independently C 1-6 alkyl, C 1-6 alkoxy, CONR 10a R 10b , halogen, cyano, S(O) 2 R 10c , SR 10d or 3 to 5-membered cycloalkyl, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 halogens;
  • R 10a , R 10b , R 10c , and R 10d are each independently H, D, or C 1-6 alkyl;
  • A is Ra is C1-6 alkyl, C3-5 cycloalkyl, halogen or cyano, wherein the C1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • B is a 5- to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
  • C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein:
  • X 1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;
  • X2 is O or a single bond
  • X 3 and X 4 are each independently C or N;
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl; or R 2a , R 2b and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl;
  • R 3 is H, D, C 1-6 alkyl, halogen or cyano, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl; or R 4 , R 5 and the carbon atom to which they are connected form a 3- to 5-membered cycloalkyl;
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is each independently C 1-6 alkyl, C 1-6 alkoxy, CONR 10a R 10b , halogen, cyano, S(O) 2 R 10c , SR 10d or 3 to 5-membered cycloalkyl, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 halogens;
  • R 10a , R 10b , R 10c , and R 10d are each independently H, D, or C 1-6 alkyl;
  • A is Ra is C1-6 alkyl, C3-5 cycloalkyl, halogen or cyano, wherein the C1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
  • C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-1) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof,
  • X 1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;
  • X2 is O
  • X 3 and X 4 are each independently C or N;
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy, cyano or SR 10d , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
  • C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof,
  • X1 is NH
  • X2 is O
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy, cyano or SR 10d , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein:
  • X1 is NH
  • X2 is O
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, cyano, or SR 10d , wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein:
  • X 1 is selected from NH
  • X2 is selected from O;
  • R 1a , R 1b are each independently selected from H, D or C 1-6 alkyl;
  • R 2a and R 2b are each independently selected from H, D or C 1-6 alkyl
  • R 3 is H, D, C 1-6 alkyl or halogen, wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 4 and R 5 are each independently H or D;
  • R 6 and R 7 are each independently H or D;
  • R 8 and R 9 are each independently H or D;
  • R 10 is CF 3 or SR 10d ;
  • R 10d is H, D or C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-2) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein:
  • X 1 is selected from NH
  • X2 is selected from O;
  • R 1a , R 1b are each independently selected from H, D or C 1-3 alkyl;
  • R 2a , R 2b are each independently selected from H, D or C 1-3 alkyl;
  • R 3 is selected from H, D or CF 3 ;
  • R 4 and R 5 are each independently selected from H or D;
  • R 6 and R 7 are each independently selected from H or D;
  • R 8 and R 9 are each independently selected from H or D;
  • R 10 is CF 3 ;
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof,
  • X 1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;
  • X2 is O
  • R 1a and R 1b are each independently H, D or C 1-6 alkyl
  • R 2a and R 2b are each independently H, D or C 1-6 alkyl
  • R 4 and R 5 are each independently H, D or C 1-6 alkyl
  • R 6 and R 7 are each independently H, D or C 1-6 alkyl
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy, cyano or SR 10d , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein:
  • X 1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;
  • X2 is O
  • R 1a and R 1b are each independently H, D or C 1-3 alkyl
  • R 2a and R 2b are each independently H, D or C 1-3 alkyl
  • R 4 and R 5 are each independently H, D or C 1-3 alkyl
  • R 6 and R 7 are each independently H, D or C 1-3 alkyl
  • R 10 is C 1-6 alkyl, cyano or SR 10d , wherein the C 1-6 alkyl is optionally substituted by 1 to 3 halogens;
  • R 10d is H, D or C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or a compound represented by formula (I-3) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein:
  • X1 is NH
  • X2 is O
  • R 1a and R 1b are each independently H, D or C 1-3 alkyl
  • R 2a and R 2b are each independently H or D;
  • R 4 and R 5 are each independently H or D;
  • R 6 and R 7 are each independently H or D;
  • R 8 and R 9 are each independently H or D;
  • R 10 is CF 3 ;
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • the PARP7 inhibitor included in the drug combination is selected from RBN-2397, ONO-7119, QLS1103, JAB-26766, NSP-5020, NSP-5033, EB400 or the following compounds or pharmaceutically acceptable salts, stereoisomers or deuterated substances thereof:
  • the CTLA-4 inhibitor included in the drug combination is selected from one or a combination of antibodies, small molecule compounds, microRNA, siRNA, and shRNA.
  • the CTLA-4 inhibitor included in the drug combination is selected from one or a combination of antibodies, small molecule compounds, microRNA, siRNA, and shRNA having CTLA-4 inhibitory activity.
  • the CTLA-4 inhibitor antibody included in the drug combination is selected from one or a combination of ipilimumab, tremelimumab, gotistobart, SHR-8068, ADG-126, ADG-116, YH-001, XTX-101, BMS-986218, porustobart, botensilimab, BA-3071, KD-6001, Zaliferelimab, Quavonlimab, REGN-4659, IMM-27M, MT-8421, BCD-145, and KN-044.
  • the platinum complex included in the drug combination is selected from one or a combination of cisplatin, carboplatin, cyclothioplatin, nedaplatin, oxaliplatin, and lobaplatin.
  • the PD-1 inhibitor or PD-L1 inhibitor included in the drug combination is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, sugemalimab, dostarlimab, cadonilimab, cemiplimab, retifanlimab, BMS-986213, HX-008, geptanolimab, prolgolimab, socazolimab, avelumab, adebrelimab, or durvalumab.
  • the PARP7 inhibitor, the CTLA-4 inhibitor and the optional PD-1 inhibitor or PD-L1 inhibitor are present in the same pharmaceutical composition, or the PARP7 inhibitor, the CTLA-4 inhibitor and the optional PD-1 inhibitor or PD-L1 inhibitor are present in different pharmaceutical compositions, respectively.
  • the drug combination comprises:
  • a first pharmaceutical composition comprising a PARP7 inhibitor and a pharmaceutically acceptable carrier and/or excipient
  • a second pharmaceutical composition comprising a CTLA-4 inhibitor and a pharmaceutically acceptable carrier and/or excipient
  • a third pharmaceutical composition comprising a PD-1 inhibitor or a PD-L1 inhibitor, and a pharmaceutically acceptable carrier and/or excipient.
  • the drug combination comprises:
  • a single pharmaceutical composition comprising a PARP7 inhibitor, a CTLA-4 inhibitor, optionally a PD-1 inhibitor or a PD-L1 inhibitor, and a pharmaceutically acceptable carrier and/or excipient.
  • the PARP7 inhibitor, the platinum complex and the optional PD-1 inhibitor or PD-L1 inhibitor are present in the same pharmaceutical composition, or the PARP7 inhibitor, the platinum complex and the optional PD-1 inhibitor or PD-L1 inhibitor are present in different pharmaceutical compositions, respectively.
  • the drug combination comprises:
  • a first pharmaceutical composition comprising a PARP7 inhibitor and a pharmaceutically acceptable carrier and/or excipient
  • a second pharmaceutical composition comprising a platinum complex and a pharmaceutically acceptable carrier and/or excipient
  • a third pharmaceutical composition comprising a PD-1 inhibitor or a PD-L1 inhibitor, and a pharmaceutically acceptable carrier and/or excipient.
  • the drug combination comprises:
  • a single pharmaceutical composition comprising a PARP7 inhibitor, a platinum complex, an optional PD-1 inhibitor or a PD-L1 inhibitor, and a pharmaceutically acceptable carrier and/or excipient.
  • One or more embodiments of the present invention provide use of the pharmaceutical combination of the present invention in treating and/or preventing solid tumors and/or blood tumors.
  • One or more embodiments of the present invention provide a method for treating and/or preventing solid tumors and/or blood tumors, comprising administering a therapeutically effective dose of the pharmaceutical combination of the present invention to a patient.
  • the PARP7 inhibitor, the CTLA- 4 inhibitor and the optional PD-1 inhibitor or PD-L1 inhibitor are administered simultaneously or separately.
  • the PARP7 inhibitor, the platinum complex and the optional PD-1 inhibitor or PD-L1 inhibitor are administered simultaneously or separately.
  • the PARP7 inhibitor in the use, is administered orally, with a frequency of three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, preferably twice a day or once a day.
  • the total daily dose of the PARP7 inhibitor is selected from 50-1500 mg, preferably 100-1000 mg, measured as the amount of free base.
  • the solid tumor is selected from breast cancer, central nervous system cancer, uterine cancer, cervical cancer, kidney cancer, adrenal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, testicular cancer, gastric cancer, head and neck cancer, laryngeal cancer, urinary tract cancer, bladder cancer, colon cancer, rectal cancer, thyroid cancer, bone cancer, epithelial cancer, bile duct cancer, gallbladder cancer, skin cancer, mesothelioma, basal cell carcinoma, adenoid cystic carcinoma, leiomyosarcoma, gastrointestinal stromal tumor, Ewing sarcoma, Kaposi sarcoma or PARP7 amplified advanced solid tumor.
  • the blood tumor is selected from leukemia, myeloma and lymphoma.
  • exemplary include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B cell lymphoma, small lymphocytic lymphoma, T cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia.
  • the lung cancer is preferably non-small cell lung cancer or neuroendocrine lung cancer.
  • the non-small cell lung cancer is preferably lung squamous cell carcinoma or lung adenocarcinoma.
  • the breast cancer is preferably hormone receptor positive (HR+) breast cancer.
  • the esophageal cancer is preferably esophageal squamous cell carcinoma or esophageal adenocarcinoma.
  • the head and neck cancer is preferably head and neck squamous cell carcinoma.
  • the uterine cancer is preferably endometrial cancer.
  • the central nervous system cancer is preferably glioma.
  • the liver cancer is preferably hepatocellular carcinoma.
  • the B-cell lymphoma is preferably diffuse large B-cell lymphoma.
  • Optional or “optionally” or “selective” or “selectively” means that the event or situation described later may but may not occur, and the description includes situations in which the event or situation occurs and situations in which it does not occur.
  • “optionally a third active ingredient PD-1 inhibitor or PD-L1 inhibitor” means that the active ingredient PD-1 inhibitor or PD-L1 inhibitor may but may not exist, and the description includes situations in which the PD-1 inhibitor or PD-L1 inhibitor exists and also includes situations in which the PD-1 inhibitor or PD-L1 inhibitor does not exist.
  • Figure 1 shows the curve of tumor volume changes in tumor-bearing mice (1).
  • Figure 2 shows the body weight change curve of tumor-bearing mice (1).
  • FIG3 shows the curve of tumor volume changes in tumor-bearing mice (2).
  • FIG4 shows the body weight change curve of tumor-bearing mice (2).
  • Compound 1 in the embodiment is compound 1 of PCT application WO2022242750, and compound 1 is prepared according to its preparation method.
  • Mouse colon cancer cells CT26 were purchased from Beina Biotechnology (Cat. No.: BNCC287983) and cultured in DMEM medium with 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C in a cell culture incubator containing 5% CO 2. When the cells were in the exponential growth phase, they were digested with trypsin, collected, counted, and inoculated.
  • CT26 cell suspension was subcutaneously inoculated on the right rib back of the mice, 1 ⁇ 10 6 cells/mouse, and the inoculation volume was 0.1 mL.
  • 48 animals were screened for inclusion in the group; they were divided into 6 groups according to the size of the tumor using the S-shaped grouping method, with 8 animals in each group.
  • the day of grouping was set as the experimental day 0 (PG-D0), and drug administration began on the first day.
  • the grouping and dosing regimen is detailed in Table 1.
  • anti-mCTLA-4 was purchased from bioxcell, clone number: 9D9, catalog number: #BP0164.
  • ig refers to intragastric administration
  • ip refers to intraperitoneal administration
  • BID refers to administration twice a day
  • BIW refers to administration twice a week
  • Q3D refers to administration once every 3 days.
  • the tumor diameter was measured with a vernier caliper twice a week, the tumor volume was calculated, and the tumor growth curve was drawn.
  • the calculation formula of tumor volume (V) was:
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent the major and minor diameters of the tumor, respectively.
  • mice were weighed twice a week.
  • compound 1 combined with anti-mCTLA-4 antibody has better in vivo anti-tumor effect than anti-mCTLA-4 antibody alone, and exhibits good safety and tolerability, indicating that the drug combination of the present invention has a significant synergistic effect.
  • compound 1 combined with cisplatin has better in vivo anti-tumor effect than cisplatin alone, and exhibits good safety and tolerability, indicating that the drug combination of the present invention has a significant synergistic effect.

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Abstract

La présente invention concerne une combinaison pharmaceutique d'un médicament combiné à un inhibiteur de PARP7, et son utilisation dans le traitement de tumeurs. La combinaison pharmaceutique comprend : un premier principe actif inhibiteur de PARP7, un deuxième principe actif inhibiteur de CTLA-4 ou complexe de platine, et éventuellement un troisième principe actif inhibiteur de PD-1 ou inhibiteur de PD-L1.
PCT/CN2024/131698 2023-11-13 2024-11-13 Combinaison pharmaceutique d'un médicament combiné à un inhibiteur de parp7, et son utilisation dans le traitement de tumeurs Pending WO2025103341A1 (fr)

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CN202311501952 2023-11-13
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CN202410332512 2024-03-22
CN202410332512.1 2024-03-22
CN202410388180 2024-04-01
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025209574A1 (fr) * 2024-04-03 2025-10-09 康百达（四川）生物医药科技有限公司 Inhibiteur de parp7 pour la prévention ou le traitement de tumeurs

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2022242750A1 (fr) * 2021-05-21 2022-11-24 成都百裕制药股份有限公司 Dérivé de pipérazine et son utilisation en médecine
CN115477640A (zh) * 2021-05-31 2022-12-16 由理生物医药（上海）有限公司 作为parp7抑制剂的哒嗪酮类化合物
TW202340175A (zh) * 2022-01-24 2023-10-16 瑞士商瑞森製藥公司 Ｐａｒｐ７抑制劑
WO2024032410A1 (fr) * 2022-08-09 2024-02-15 成都百裕制药股份有限公司 Composition à base d'un composé pipérazine et d'un inhibiteur de pd-1 ou d'un inhibiteur de pd-l1 et son utilisation dans le traitement de tumeurs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2022242750A1 (fr) * 2021-05-21 2022-11-24 成都百裕制药股份有限公司 Dérivé de pipérazine et son utilisation en médecine
CN115477640A (zh) * 2021-05-31 2022-12-16 由理生物医药（上海）有限公司 作为parp7抑制剂的哒嗪酮类化合物
TW202340175A (zh) * 2022-01-24 2023-10-16 瑞士商瑞森製藥公司 Ｐａｒｐ７抑制劑
WO2024032410A1 (fr) * 2022-08-09 2024-02-15 成都百裕制药股份有限公司 Composition à base d'un composé pipérazine et d'un inhibiteur de pd-1 ou d'un inhibiteur de pd-l1 et son utilisation dans le traitement de tumeurs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025209574A1 (fr) * 2024-04-03 2025-10-09 康百达（四川）生物医药科技有限公司 Inhibiteur de parp7 pour la prévention ou le traitement de tumeurs

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