Bioorganic & medicinal chemistry · 2021
Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton.
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Wang Bin, Feng Weiwei, Wang Jinan, Dong Yuanzhen, Liu Yanlong, Yao Yiyan, Zhang Jianqing, Shi Wei, Liu Limin, Zhang Hongying, He Xiangyi, Chang Xiayun, Wang Xiaojin, Xu Hongjiang, Liu Fei, Feng Jun
Аннотация
The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.