CN-121971611-A - Medicament for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation, composition, preparation method and application thereof

Abstract

The invention discloses a medicine for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation, a composition, a preparation method and application thereof, and belongs to the technical fields of antitumor medicines and metabolism regulation medicines. The composition comprises an FA2H catalytic product, an SCD1 inhibitor and an FASN inhibitor, and obviously reduces the proliferation rate and migration capacity of gastric cancer cells by synergistically inhibiting the ingestion, synthesis and oxidative metabolism of fatty acid. The invention solves the core problems of easy escape of single target inhibition, high chemical resistance, difficult clinical transformation and the like in the prior art.

Inventors

• SU XIONG
• FENG MIN
• LIU JINGJING

Assignees

• 苏州大学

Dates

Publication Date

20260505

Application Date

20251231

Claims (8)

1. 1. A drug for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation, which is characterized by comprising an FA2H catalytic product.
2. 2. The drug for inhibiting gastric cancer cell proliferation according to claim 1, wherein the FA2H catalytic product is (R) -2-hydroxy fatty acid or a pharmaceutically acceptable salt thereof.
3. 3. A composition comprising the drug for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation according to claim 1 or 2, further comprising a fatty acid metabolism inhibitor selected from the group consisting of SCD1 inhibitor and FASN inhibitor, wherein the molar ratio of the FA2H catalytic product to SCD1 inhibitor to FASN inhibitor is 1:0.02-0.05:0.1-0.5.
4. 4. A pharmaceutical composition according to claim 3, wherein the SCD1 inhibitor is a939572 and the FASN inhibitor is TVB-2640.
5. 5. The pharmaceutical composition of claim 3, wherein the FA2H catalytic product has a concentration of 10-50 μm, the SCD1 inhibitor has a concentration of 100-500 nm, and the FASN inhibitor has a concentration of 5-20 μm.
6. 6. The pharmaceutical composition of claim 3, wherein the composition further comprises a CD36 targeting nucleic acid sequence.
7. 7. A method of preparing the pharmaceutical composition of any one of claims 3-6, comprising the steps of: (1) Dissolving the FA2H catalysis product in DMSO to prepare a FA2H catalysis product mother solution; (2) The SCD1 inhibitor and the FASN inhibitor are respectively dissolved in DMSO to prepare SCD1 inhibitor and FASN inhibitor mother liquor.
8. 8. Use of an A2H catalytic product according to claim 1 or 2 in the manufacture of a medicament for inhibiting gastric cancer cell proliferation by inhibiting palmitoylation modification and/or cell membrane localization of CD 36.

Description

Medicament for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation, composition, preparation method and application thereof Technical Field The invention relates to a medicine for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation, a composition, a preparation method and application thereof, and belongs to the technical fields of antitumor medicines and metabolism regulation medicines. Background Gastric cancer is one of malignant tumors with highest mortality rate in the global scope, and the treatment means of gastric cancer is limited by the core problems of difficult early diagnosis, easy metastasis in late stage, strong drug resistance and the like for a long time. Although the surgical excision has remarkable effect on early gastric cancer, most patients already progress to late stage when diagnosed, and the traditional chemotherapy and targeted therapy have the problems of tumor microenvironment heterogeneity, metabolic reprogramming escape mechanism, drug toxicity accumulation and the like, so that the clinical curative effect is limited and the survival period is difficult to break through for one year. The prior art reveals key effects of fatty acid metabolism in gastric cancer proliferation and metastasis, cancer cells maintain malignant phenotype by excessively relying on fatty acid oxidation energy supply, membrane lipid synthesis and signal molecule modification, but an intervention strategy aiming at the pathway still has major bottlenecks that firstly, single target inhibition is easy to trigger compensatory metabolism bypass activation, so that curative effect is short and dynamic uptake of fatty acid in tumor microenvironment cannot be blocked, secondly, the effect of posttranslational modification mechanism of key regulatory protein in gastric cancer is not fully analyzed, the prior art is limited to basic research, a feasible scheme for converting the mechanism into clinical treatment is lacking, and dynamic balance regulation of palmitoylation modification is not established in gastric cancer, thirdly, a multi-target cooperative inhibition strategy aiming at a fatty acid metabolic pathway is not established, the existing drug combination is easy to cause normal cell metabolism toxicity due to lack of integration of membrane transport protein positioning and functional regulation, and the traditional drug resistance problem is outstanding, the mechanism of the traditional drug has cross defense with oxidation resistance mediated by oxidative stress cancer cells, the mechanism and the oxidative resistance metabolism of fatty acid metabolism is not fully analyzed, the existing scheme is not found, the clinical scheme is not verified by the research of the scheme is high in clinical selective, and the clinical scheme is not verified, and the clinical scheme is not has great enough to be verified. Furthermore, prior art studies on the function of fatty acid hydroxylases have focused on neurodegenerative diseases or skin barrier repair, whose role in tumor metabolic remodeling is not yet clear, and there is no evidence that activation of such enzymes could interfere with membrane protein function or remodel the tumor microenvironment. In summary, the prior art fails to solve the following core problems of (1) how to synergistically inhibit fatty acid uptake, synthesis and oxidative metabolism to fully block cancer cell energy supply, (2) how to precisely regulate posttranslational modification of key membrane proteins to limit their functions, (3) how to design low-toxicity and high-efficiency drug combinations to overcome chemotherapy resistance and improve clinical response rate, and (4) how to establish a complete evidence chain from molecular mechanism to animal model to verify feasibility of multi-target metabolic intervention. The most core problems include easy escape of single target inhibition, lack of accurate regulation and control means for CD36 membrane positioning, and the like. These bottlenecks severely hamper the development and application of gastric cancer treatment strategies based on fatty acid metabolic regulation. Disclosure of Invention Aiming at the defects in the prior art, the invention provides a drug for inhibiting gastric cancer cell proliferation based on fatty acid metabolism regulation, which comprises an FA2H catalytic product. Preferably, the FA2H catalytic product is (R) -2-hydroxy fatty acid or a pharmaceutically acceptable salt thereof. The invention also provides a composition comprising the drug for inhibiting gastric cancer cell proliferation, and further comprising a fatty acid metabolism inhibitor, wherein the fatty acid metabolism inhibitor is selected from a combination of an SCD1 inhibitor and a FASN inhibitor, and the molar ratio of the FA2H catalytic product to the SCD1 inhibitor to the FASN inhibitor is 1:0.02-0.05:0.1-0.5. Preferably, the SCD1 inhibitor is A939572 and the F