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CN-121971629-A - Pharmaceutical composition for combined administration of JNK inhibitor and PARG inhibitor and pharmaceutical application

CN121971629ACN 121971629 ACN121971629 ACN 121971629ACN-121971629-A

Abstract

The invention discloses a pharmaceutical composition for combined administration of a JNK inhibitor and a PARG inhibitor and pharmaceutical application thereof. The invention discloses the invention for the first time, the invention discovers that the JNK inhibitor (such as the present tower Ma Mo) and the PARG inhibitor (such as the PDD 00017273) have synergistic effect when being used for improving the synergistic effect of treating gastric cancer, the synergistic effect is achieved when the two inhibitors are used together, the remarkable improvement of the anti-tumor effect is realized, and the toxicity to each organ is not increased through the combination, but the dosage of various medicines is reduced, so that the toxic and side effects are reduced, and the invention has remarkable significance for the gastric cancer resistance application of the combination of the PARG inhibitor and the JNK inhibitor.

Inventors

  • YE ZU
  • CHENG XIANGDONG
  • He Handie
  • ZHONG YUKE
  • DU XIAOHAN
  • You Chenlong
  • Lu Rihui

Assignees

  • 中国科学院杭州医学研究所

Dates

Publication Date
20260505
Application Date
20260407

Claims (9)

  1. The pharmaceutical composition for combined use of the JNK inhibitor and the PARG inhibitor is characterized in that the pharmaceutical composition is used for resisting tumors, and the types of the tumors are gastric cancer, lung cancer, colon cancer, liver cancer, pancreatic cancer, breast cancer or esophageal cancer.
  2. 2. The pharmaceutical composition of claim 1, wherein the JNK inhibitor is at least one of BSJ-04-122, DB07268, and present tower Ma Mozhong.
  3. 3. The pharmaceutical composition according to claim 2, wherein the concentration of BSJ-04-122 in JNK inhibitor is not lower than 2 μΜ, DB07268 is not lower than 0.2 μΜ, and tower Ma Mo is not lower than 10 μΜ.
  4. 4. The pharmaceutical composition of claim 1, wherein the PARG inhibitor is PDD00017273.
  5. 5. The pharmaceutical composition according to claim 4, wherein the PARG inhibitor is used at a concentration of not less than 10 μm.
  6. The pharmaceutical application of a pharmaceutical composition for combined use of a JNK inhibitor and a PARG inhibitor is characterized in that the pharmaceutical composition is used for preparing an anti-tumor drug, and the tumor type is gastric cancer, lung cancer, colon cancer, liver cancer, pancreatic cancer, breast cancer or esophageal cancer.
  7. 7. The pharmaceutical use of claim 6, wherein the JNK inhibitor is at least one of BSJ-04-122, DB07268, and present tower Ma Mozhong.
  8. 8. The pharmaceutical use according to claim 6, wherein the PARG inhibitor is PDD00017273.
  9. 9. The use of claim 6, wherein the combination is administered by at least one of intratumoral injection, peritumoral injection, intravenous injection and oral administration.

Description

Pharmaceutical composition for combined administration of JNK inhibitor and PARG inhibitor and pharmaceutical application Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a pharmaceutical composition for combined administration of a JNK inhibitor and a PARG inhibitor and pharmaceutical application thereof. Background Gastric cancer (GASTRIC CANCER, GC) is the fifth most common worldwide in cancer morbidity and mortality, and its treatment includes surgery, chemotherapy, immunization, targeting, etc. In recent years, the targeting therapy not only changes the therapeutic pattern of gastric cancer, but also becomes an important research direction of the whole solid tumor therapy, and the core is to realize efficient identification and elimination of tumor cells through targeting molecules. However, like many other cancers, existing single targeted therapies are prone to drug resistance in the treatment of gastric cancer, and the beneficiary population of single targeted drugs is relatively limited due to the high heterogeneity of tumors, leading to poor efficacy or eventual progression in some patients. Therefore, the multi-target combined therapy is explored to overcome drug resistance, enhance the anti-tumor targeting effect and enlarge the beneficiary population, and the multi-target combined therapy gradually becomes an important research direction in the treatment of gastric cancer and even carcinoma. Synthetic lethality is the phenomenon in which two genes (A and B) are inactivated simultaneously resulting in cell death, whereas cells survive when either gene is inactivated alone. When the tumor cells carry BRCA1/2 mutation (homologous recombination repair defect, HRD), the stability of DNA is maintained by means of poly (ADP-ribose) polymerase (PARP) -mediated Base Excision Repair (BER), and the BRCA1/2 mutant tumor cells can be killed in a targeted manner by using a PARP inhibitor. Poly (ADP-ribose) glycohydrolase, PARG and PARP dynamically control the synthesis and degradation of ADP-ribose polymers (PAR chains) to maintain genomic stability. Inactivation of PARG can lead to deposition of PAR chains, retention of repair proteins on DNA, stunted DNA replication processes, and even DNA double strand breaks. Current studies of PARG inhibitors have entered the clinical transformation stage and several PARG inhibitors have entered the clinical trial stages such as IDE-161, ETX-19477, DAT-2645. Although PARP inhibitors have been used in clinical therapy, drug resistance is likely to occur, whereas tumor cells are killed by PARG inhibitors, which not only widens the therapeutic window of PARP inhibitors, but also provides insight for use with other therapeutic agents. JNK (c-Jun N-TERMINAL KINASE) is a mitogen-activated protein kinase (MAPK) family member, and plays a key regulatory role in the processes of cell stress reaction, apoptosis, inflammation, proliferation and the like. In tumors, JNK signals are often abnormally activated and are involved in maintaining tumor cell survival and drug resistance. JNK inhibitors as a class of compounds targeting the c-Jun N-terminal kinase, the development of which has made a series of advances in the fields of tumor, inflammation and neurodegenerative diseases. In tumor treatment, the JNK pathway is an important target point because of the core effects of the JNK pathway in stress reaction, apoptosis regulation and chemotherapy drug resistance, and no JNK inhibitor is singly used for gastric cancer in batches at present, but a large number of preclinical researches show that the JNK pathway can obviously enhance the anti-tumor effects of various chemotherapy drugs (such as platinum and beta Ma Mo) and targeted drugs, and has definite effects especially in the aspects of inducing apoptosis and overcoming drug resistance. In the aspect of clinical research, a plurality of JNK inhibitors enter clinical test stages, such AS AS602801, CC-930 and the like, and although the research is not concentrated in the field of gastric cancer, the JNK inhibitors have tolerability and preliminary activity in human bodies, and provide important clinical basis and safety data reference for the expansion of the JNK inhibitors to gastric cancer combined treatment. Disclosure of Invention The invention provides a pharmaceutical composition for combined administration of a JNK inhibitor and a PARG inhibitor and pharmaceutical application thereof aiming at the defects in the prior art. CRISPR screening (using GECKO V2 whole genome knockout library) based on synthetic lethal effects revealed that, among the prominent targets of combined mortality with PARG inhibitors, the top-ranked key components including MEK4, MEK7 and MAPK8 all belong to the MEK4/7-JNK1 signaling pathway—this finding not only suggested mechanically that the JNK pathway is a key break to enhance the efficacy of PARG inhibitors, but also directed towards JNK