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Discovery of novel indazole-acylsulfonamide hybrids as selective Mcl-1 inhibitors
Yichao Wan1, Yuanhua Li1, Chunxing Yan1
1Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, Hunan University of Science and Technology, Xiangtan, Hunan 411201, PR China; Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan Provincial Key Lab of Advanced Materials for New Energy Storage and Conversion, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, PR China.
Abstract:
Overexpressing myeloid cell leukemia sequence 1 (Mcl-1) protein is an important way to confer the resistance of cancer cells to conventional anti-cancer treatments. Therefore, developing Mcl-1 inhibitors has become an attractive strategy for cancer therapy. In the studies, a series of new indazole-acylsulfonamide hybrids were designed, synthesized and evaluated as potent Mcl-1 inhibitors. Among them, the most potent compound 17 (Ki = 0.43 μM) showed a little better inhibitory activity against Mcl-1 protein than positive control AT-101 (Ki = 0.45 μM). Pleasingly, it displayed > 40-fold selectivity over Bcl-2 (Ki = 18 μM) and Bcl-xL (no activity). Furthermore, compound 17 had good inhibitory activities against PC-3, MDA-MB-231 and K562 cells (IC50 = 12.3, 10.6 and 6.62 μM, respectively) and could effectively induce apoptosis and the activation of caspase-3 in a dose-dependent manner in K562 cells.
