Discovery of a novel BCL-2 inhibitor GW806742X for the treatment of TNBC

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-04-06 DOI:10.1016/j.bcp.2025.116925

Wenjun Liu , Jia Xu , Li Chen , Dongze Zhang , Juan Zhang , Linlin Lu , Xiaoming Zhang , Xue Huang , Guangbo Zhang

{"title":"Discovery of a novel BCL-2 inhibitor GW806742X for the treatment of TNBC","authors":"Wenjun Liu , Jia Xu , Li Chen , Dongze Zhang , Juan Zhang , Linlin Lu , Xiaoming Zhang , Xue Huang , Guangbo Zhang","doi":"10.1016/j.bcp.2025.116925","DOIUrl":null,"url":null,"abstract":"<div><div>Triple-negative breast cancer（TNBC） lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), and traditional treatments cannot accurately target TNBC. Anthracycline- and paclitaxel-based chemotherapeutic agents are still the mainstay of treatment for TNBC, but these chemotherapeutic agents have major toxic side effects and are prone to drug resistance during the treatment of TNBC. In this study, we investigated the efficacy and potential mechanisms of action of GW806742X in the treatment of TNBC.</div><div>We screened a library of 600 FDA-approved small molecule compounds to identify GW806742X, a small molecule that inhibits the viability of triple-negative breast cancer cells. In vitro, GW806742X was found to be cytotoxic to TNBC cells in a dose-dependent manner and to inhibit the growth of MDA-MB-468 tumors in vivo. Mechanistically, we used PharmMapper to predict the possible targets of GW806742X and demonstrated that the small molecule drug could directly bind to BCL-2 by molecular docking simulations and ITC experiments. Western blot analysis demonstrated that GW806742X could reduce BCL-2 protein levels and possibly promote BCL-2 degradation through the lysosomal pathway. Moreover, GW806742X disrupts NF-κB signaling.</div><div>In conclusion, this study demonstrates that GW806742X can be a potential therapeutic agent for triple-negative breast cancer by targeting BCL-2.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116925"},"PeriodicalIF":5.3000,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S000629522500187X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Triple-negative breast cancer（TNBC） lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), and traditional treatments cannot accurately target TNBC. Anthracycline- and paclitaxel-based chemotherapeutic agents are still the mainstay of treatment for TNBC, but these chemotherapeutic agents have major toxic side effects and are prone to drug resistance during the treatment of TNBC. In this study, we investigated the efficacy and potential mechanisms of action of GW806742X in the treatment of TNBC.

We screened a library of 600 FDA-approved small molecule compounds to identify GW806742X, a small molecule that inhibits the viability of triple-negative breast cancer cells. In vitro, GW806742X was found to be cytotoxic to TNBC cells in a dose-dependent manner and to inhibit the growth of MDA-MB-468 tumors in vivo. Mechanistically, we used PharmMapper to predict the possible targets of GW806742X and demonstrated that the small molecule drug could directly bind to BCL-2 by molecular docking simulations and ITC experiments. Western blot analysis demonstrated that GW806742X could reduce BCL-2 protein levels and possibly promote BCL-2 degradation through the lysosomal pathway. Moreover, GW806742X disrupts NF-κB signaling.

In conclusion, this study demonstrates that GW806742X can be a potential therapeutic agent for triple-negative breast cancer by targeting BCL-2.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.