2. Academic Validation
  3. Discovery of a novel BCL-2 inhibitor GW806742X for the treatment of TNBC

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

  • Biochem Pharmacol. 2025 Jul:237:116925. doi: 10.1016/j.bcp.2025.116925.
Wenjun Liu 1,  Jia Xu 1,  Li Chen 2,  Dongze Zhang 2,  Juan Zhang 2,  Linlin Lu 3,  Xiaoming Zhang 4,  Xue Huang 5,  Guangbo Zhang 6
Affiliations

Affiliations

  • 1 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China; School of Life Science, Soochow University, China.
  • 2 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
  • 3 Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: lulinlin@suda.edu.cn.
  • 4 Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, China. Electronic address: xmzhang@siii.cas.cn.
  • 5 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China. Electronic address: huangxue2021@suda.edu.cn.
  • 6 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China. Electronic address: zhangguangbo@suda.edu.cn.
PMID: 40199403 DOI: 10.1016/j.bcp.2025.116925
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.

Keywords

Apoptosis; BCL-2; GW806742X; NF-κB; Small-molecule inhibitor; TNBC.

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