Structure-activity relationship studies on Bax activator SMBA1 for the treatment of ER-positive and triple-negative breast cancer.

ID: ALA4364270

Journal: Eur J Med Chem

Title: Structure-activity relationship studies on Bax activator SMBA1 for the treatment of ER-positive and triple-negative breast cancer.

Authors: Liu G, Yin T, Kim H, Ding C, Yu Z, Wang H, Chen H, Yan R, Wold EA, Zou H, Liu X, Ding Y, Shen Q, Zhou J.

Abstract: In an effort to develop novel Bax activators for breast cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC₅₀ values of 3.22 μM and 0.07 μM against triple-negative breast cancer MDA-MB-231 and 3.81 μM and 0.06 μM against ER-positive breast cancer MCF-7 cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to cancer cell apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast cancer.

CiteXplore: 31220676

DOI: 10.1016/j.ejmech.2019.06.004

Patent ID: ┄