CN-121971628-A - Application of VCP inhibitor combined with HDAC inhibitor in preparation of anti-pancreatic cancer drugs

Abstract

The invention discloses an application of a VCP inhibitor combined with an HDAC inhibitor in preparing an anti-pancreatic cancer drug, and belongs to the technical field of medicines. The invention proves that the VCP inhibitor and the HDAC inhibitor have synergistic effect in treating pancreatic cancer for the first time, especially for pancreatic cancer cells insensitive to the HDAC inhibitor, the VCP inhibitor can enhance the chemosensitivity of the pancreatic cancer to the HDAC inhibitor, so that the application of the VCP inhibitor and the HDAC inhibitor in preparing medicaments for preventing and/or treating pancreatic cancer is provided, and a better choice is provided for treating pancreatic cancer, so that the application value is provided.

Inventors

• ZHU HONG
• YANG BO
• HE QIAOJUN
• YUAN TAO
• LIU PENG

Assignees

• 浙江大学
• 浙江大学智能创新药物研究院

Dates

Publication Date

20260505

Application Date

20260209

Claims (10)

1. Use of a vcp inhibitor for the preparation of an HDAC inhibitor anti-pancreatic cancer sensitizer.
2. Use of a vcp inhibitor in combination with an HDAC inhibitor for the preparation of a medicament for the prevention and/or treatment of pancreatic cancer.
3. 3. The use of claim 2, wherein the pancreatic cancer is a pancreatic cancer that is insensitive to HDAC inhibitors.
4. 4. The use according to claim 2 or 3, wherein the HDAC inhibitor is Mo Nuosi ta or cidamine.
5. 5. Use according to claim 2 or 3, wherein the VCP inhibitor is CB-5339.
6. 6. A pharmaceutical composition for treating pancreatic cancer, comprising a first formulation of a VCP inhibitor as an active ingredient and a pharmaceutically acceptable carrier, and a second formulation of an HDAC inhibitor as an active ingredient and a pharmaceutically acceptable carrier.
7. 7. The pharmaceutical composition of claim 6, wherein the VCP inhibitor is CB-5339 and the HDAC inhibitor is Mo Nuosi ta or cidamine.
8. 8. The pharmaceutical composition of claim 7, wherein the molar ratio of CB-5339 to Mo Nuosi is 0.05 to 0.2:1 or 0.15 to 0.2:0.5 to 1 or 0.1:0.75 to 1.
9. 9. The pharmaceutical composition of claim 7, wherein the molar ratio of CB-5339 to cidamine is from 0.05 to 0.2:1.5 to 2.
10. 10. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in the form of an oral formulation.

Description

Application of VCP inhibitor combined with HDAC inhibitor in preparation of anti-pancreatic cancer drugs Technical Field The invention relates to the technical field of medicines, in particular to application of a VCP inhibitor combined with an HDAC inhibitor in preparation of an anti-pancreatic cancer medicine. Background Pancreatic Cancer (PC) is a malignant tumor originating from pancreatic ductal epithelium and acinar cells, and has hidden onset of pancreatic cancer, and is atypical in early clinical symptoms of patients, and when obvious symptoms exist, the patients already belong to middle and late stages, and the opportunity of surgical treatment is lost. Because of its invasive nature and limited treatment options, it is one of the most difficult to control malignancies, with a patient survival rate of less than 10% for 5 years, known by the medical community as "king in cancer". Histone deacetylases (Histone deacetylases, HDACs) are zinc-dependent enzymes that play a critical role in regulating gene expression by removing acetyl groups from lysine residues on core histones. HDACs play a key role in controlling cancer cell processes such as proliferation, migration, angiogenesis, immune evasion, and the like. Abnormal expression of HDAC was found in both pancreatic and gastric cancers, and this was used as a potential target in tumor treatment (Xiang X S, et al 2022;Espinoza A F, et al 2024). Heretofore, FDA (Food and Drug Administration) has approved various HDAC inhibitors such as cibutamine (Tucidinostat), vorinostat (Vorinostat), romidepsin (Romidepsin), mo Nuosi he (Mocetinostat), etc., but only has a better anti-tumor effect among hematological tumors in current reports, and has not yet had a good anti-tumor effect on the treatment of solid tumors. How to improve the antitumor effect of pancreatic cancer and overcome the drug resistance of tumor cells is a difficulty and a hot spot of pancreatic cancer treatment. VCP (valin-containing protein), also known as P97, plays an important role in a variety of cellular functions, including protein quality control, endoplasmic reticulum-associated degradation (ERAD), and the like. VCP is abnormally expressed in various tumor tissues and is closely related to the occurrence and prognosis of cholangiocarcinoma, pancreatic cancer (Zhang P, et al 2025; wang J, et al 2021). Thus, VCP has been anti-tumor as a potential target, and various types of inhibitors have been developed, including ATP competitive inhibitors, allosteric inhibitors, and covalent inhibitors. Currently, inhibitors that have been subjected to clinical studies include CB-5083 and CB-5339, wherein CB-5339 has a better antitumor activity against hematological malignancies (Roux B, et al 2021) and has a molecular formula of C 24 H24 N6 O. There is no report on the study of the combination of VCP inhibitors and HDAC inhibitors for the prevention and/or treatment of pancreatic cancer. Disclosure of Invention The invention aims to provide a pharmaceutical composition capable of effectively improving the treatment effect of pancreatic cancer, in particular to pancreatic cancer insensitive to an HDAC inhibitor, so as to solve the problems of poor curative effect, drug resistance and the like of pancreatic cancer patients in the treatment process in the prior art. In order to achieve the above purpose, the invention adopts the following technical scheme: The invention provides an application of a VCP inhibitor in preparing an HDAC inhibitor anti-pancreatic cancer sensitizer. The present inventors have found that VCP inhibitors such as CB-5339 are capable of sensitizing the inhibitory activity of HDAC inhibitors on pancreatic cancer cell proliferation, thereby enhancing the therapeutic effect of HDAC inhibitors on pancreatic cancer. The invention provides an application of a VCP inhibitor and an HDAC inhibitor in preparing medicines for preventing and/or treating pancreatic cancer. The invention researches find that the combination of the HDAC inhibitor and the VCP inhibitor plays a synergistic role in resisting pancreatic cancer and inducing tumor cell apoptosis, so the invention provides a novel treatment method of the pancreatic cancer by combining the VCP inhibitor and the HDAC inhibitor. Further, the pancreatic cancer is a pancreatic cancer that is insensitive to HDAC inhibitors. The research of the invention discovers that the VCP inhibitor can enhance the chemosensitivity of the pancreatic cancer insensitive to the HDAC inhibitor, and solves the problem that the pancreatic cancer patient is insensitive to or resistant to the HDAC inhibitor. In the present invention, the HDAC inhibitor may be a substance that inhibits the activity of an HDAC protein, or a substance that degrades the activity of an HDAC protein, or a gene tool that reduces the level of an HDAC protein. Further, the HDAC inhibitor is Mo Nuosi ta or cidamine. In the present invention, the VCP inhibitor may be a substance that inh