CN-121971423-A - MTA3 small molecule inhibitor and application thereof in sensitization of gemcitabine pancreatic duct adenocarcinoma chemotherapy effect

Abstract

The invention relates to the technical field of biological medicines, in particular to an MTA3 small molecule inhibitor and application thereof in sensitization of gemcitabine pancreatic duct adenocarcinoma chemotherapy effects. The invention provides a small molecule MTA3i-01 obtained through high-throughput virtual screening and structure optimization. The small molecule MTA3i-01 provided by the invention can specifically interfere the combination of MTA3 protein and CRIP2 gene promoter region, effectively restore the sensitivity of tumor cells to gemcitabine, thereby obviously enhancing the curative effect of chemotherapy. And the combined treatment of MTA3i-01 and gemcitabine can obviously inhibit tumor growth, is obviously superior to a gemcitabine single drug group and an MTA3i-01 single drug group, and does not observe obvious toxic reaction, so that the combined scheme has good in vivo safety and synergistic curative effect.

Inventors

• WU LIANGLIANG
• WANG BAOGUI
• WANG XIAONA

Assignees

• 天津市肿瘤医院（天津医科大学肿瘤医院）

Dates

Publication Date

20260505

Application Date

20260318

Claims (7)

1. 1. The MTA3 small molecule inhibitor is characterized in that the structure of the MTA3 small molecule inhibitor is shown as a formula (I): Formula (I).
2. 2. A pharmaceutical composition comprising the small molecule MTA3 inhibitor of claim 1 and a pharmaceutically acceptable carrier or adjuvant.
3. 3. The pharmaceutical composition according to claim 2, wherein, the pharmaceutical composition further comprises gemcitabine.
4. 4. The pharmaceutical composition of claim 3, wherein the concentration of the MTA3 small molecule inhibitor in the pharmaceutical composition is 4-6 μΜ, and the concentration of the gemcitabine in the pharmaceutical composition is 8-12 nM.
5. 5. Use of the small molecule MTA3 inhibitor of claim 1 or the pharmaceutical composition of any one of claims 2-4 in the manufacture of a medicament for the treatment of pancreatic ductal adenocarcinoma.
6. 6. Use of the small molecule MTA3 inhibitor of claim 1 for sensitizing the effects of chemotherapy on gemcitabine pancreatic ductal adenocarcinoma.
7. 7. The use of claim 6, wherein the pancreatic ductal adenocarcinoma is gemcitabine resistant or pancreatic ductal adenocarcinoma at risk of drug resistance.

Description

MTA3 small molecule inhibitor and application thereof in sensitization of gemcitabine pancreatic duct adenocarcinoma chemotherapy effect Technical Field The invention relates to the technical field of biological medicines, in particular to an MTA3 small molecule inhibitor and application thereof in sensitization of gemcitabine pancreatic duct adenocarcinoma chemotherapy effects. Background Pancreatic ductal adenocarcinoma (PANCREATIC DUCTAL ADENOCARCINOMA, PDAC) is one of the most malignant tumors of the digestive tract, and patients have a survival rate of about 10% after 5 years long wander due to its early diagnosis difficulty, rapid progression, susceptibility to metastasis and resistance to treatment. About 80% of patients already have advanced locally or have undergone distant metastasis at the time of diagnosis, losing the opportunity for radical surgery, and chemotherapy has become a major systemic treatment. Gemcitabine (Gemcitabine, GEM) as a nucleoside analog of deoxycytidine has long been the cornerstone of standard chemotherapy regimens for PDACs. However, primary or acquired resistance of tumor cells to gemcitabine, either as a single agent or in combination, is the leading cause of treatment failure. Currently, there has been some progress in the study of gemcitabine resistance mechanisms, including abnormal drug-metabolizing enzymes, activation of anti-apoptotic pathways, tumor microenvironment (e.g., CAFs) effects, epithelial-to-mesenchymal transition (EMT), hypoxia, and the like. Despite the variety of sensitization strategies, the overall response rate is still low, and new targets for action are urgently needed. Although various sensitization strategies (e.g., combined use of aspirin, metformin, nidulans, etc.) have been developed for the above mechanisms, the overall response rate of gemcitabine in clinical trials remains low. This suggests that there may be yet to be fully appreciated, critical drug-resistant driver genes and signaling pathways. Therefore, the systematic screening and identification of new drug-resistance related targets using new technological means is critical for the development of more effective combination treatment protocols. In recent years, CRISPR/Cas9 gene editing techniques, particularly library screening based on CRISPR activation (CRISPRa) or inhibition (CRISPRi), have become powerful tools for the discovery of drug resistance or susceptibility genes across the genome. By constructing a library of sgrnas targeting all genes, positive/negative selection under drug pressure can efficiently and unbiased identify key genes associated with a particular phenotype. Our earlier studies were directed to the systematic screening of genes that confer cell resistance in gemcitabine-treated PDAC cell lines using whole genome CRISPRa activation libraries. As a result of the screening, MTA3 was found to be one of the most highly enriched genes. Further bioinformatic analysis showed that, among hundreds of cancer cell lines, MTA3 mRNA expression levels were significantly positively correlated with IC50 values for gemcitabine. Analysis of clinical samples (94 PDAC patients receiving gemcitabine-assisted chemotherapy) further demonstrated that high MTA3 expression was associated with significant reductions in total survival (OS) and relapse-free survival (RFS) in the patients. Mechanically, MTA3 is a key component of the Mi-2/nucleosome remodeling and deacetylation (Mi-2/NuRD) transcriptional repression complex. MTA3 was found to function by directly binding to and transcribing the promoter region of the CRIP2 (Cysteine-Rich Protein 2) gene. CRIP2 is a protein with tumor-inhibiting function known to bind to and inhibit the transcriptional activity of the NF- κB/p65 subunit. Thus, upregulation of MTA3 results in a decrease in CRIP2 expression, thereby alleviating inhibition of NF- κB/p65 signaling, activating downstream pro-survival, anti-apoptotic genes, ultimately inducing gemcitabine resistance. Furthermore, gemcitabine treatment itself is capable of modulating expression of MTA3 in a feedback manner by activating STAT3 signaling pathway, thereby mediating the development of acquired drug resistance. However, although the key role of MTA3 in PDAC gemcitabine resistance has been primarily elucidated, no clinically useful small molecule inhibitors specifically targeting MTA3 are currently available. Based on the above findings and unmet clinical needs, the present invention aims to design and develop a small molecule inhibitor capable of specifically and efficiently targeting MTA3 protein and directly blocking its function. The inhibitor aims at directly interfering the function of MTA3 in a NuRD complex or the interaction of the MTA3 with DNA/protein, so as to reverse the gemcitabine resistance mediated by MTA3, and provides a brand-new combined chemotherapy sensitization strategy with definite mechanism for PDAC patients. Disclosure of Invention The invention aims to solve