A novel Mcl-1 inhibitor synergizes with venetoclax to induce apoptosis in cancer cells

Molecular Medicine

Research Article

Fangshu Liu¹  Hui Zeng¹  Huien Zhan¹  Tianming Zhao¹  Shurong Xie¹  Qiang He²  Shengbin Lin²  Guo Chen³  Cheng Jiang⁴  Cong Wang⁵ 

[1] Department of Hematology, The First Affiliated Hospital of Jinan University, 510630, Guangzhou, China;Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, 510632, Guangzhou, China;Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, 510632, Guangzhou, China;School of Biopharmacy, China Pharmaceutical University, 211198, Nanjing, China;Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 210009, Nanjing, China;School of Biopharmacy, China Pharmaceutical University, 211198, Nanjing, China;

关键词: Mcl-1 inhibitor;    Bcl-2;    Venetoclax;    Apoptosis;    AML;   

DOI  :  10.1186/s10020-022-00565-7

 received in 2022-09-20, accepted in 2022-11-03,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundEvading apoptosis by overexpression of anti-apoptotic Bcl-2 family proteins is a hallmark of cancer cells and the Bcl-2 selective inhibitor venetoclax is widely used in the treatment of hematologic malignancies. Mcl-1, another anti-apoptotic Bcl-2 family member, is recognized as the primary cause of resistance to venetoclax treatment. However, there is currently no Mcl-1 inhibitor approved for clinical use.MethodsPaired parental and Mcl-1 knockout H1299 cells were used to screen and identify a small molecule named MI-238. Immunoprecipitation (IP) and flow cytometry assay were performed to analyze the activation of pro-apoptotic protein Bak. Annexin V staining and western blot analysis of cleaved caspase 3 were employed to measure the cell apoptosis. Mouse xenograft AML model using luciferase-expressing Molm13 cells was employed to evaluate in vivo therapeutic efficacy. Bone marrow samples from newly diagnosed AML patients were collected to evaluate the therapeutic potency.ResultsHere, we show that MI-238, a novel and specific Mcl-1 inhibitor, can disrupt the association of Mcl-1 with BH3-only pro-apoptotic proteins, selectively leading to apoptosis in Mcl-1 proficient cells. Moreover, MI-238 treatment also potently induces apoptosis in acute myeloid leukemia (AML) cells. Notably, the combined treatment of MI-238 with venetoclax exhibited strong synergistic anti-cancer effects in AML cells in vitro, MOLM-13 xenografts mouse model and AML patient samples.ConclusionsThis study identified a novel and selective Mcl-1 inhibitor MI-238 and demonstrated that the development of MI-238 provides a novel strategy to improve the outcome of venetoclax therapy in AML.

【 授权许可】

CC BY   
© The Author(s) 2023

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