Discovery of novel indazole-acylsulfonamide hybrids as selective Mcl-1 inhibitors.
Discovery of novel indazole-acylsulfonamide hybrids as selective Mcl-1 inhibitors.
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DOI：
10.1016/j.bioorg.2020.104217
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发表时间：
2020-08
影响因子：
5.1
通讯作者：
Yichao Wan;Yuanhua Li;Chunxing Yan;Jiajun Wen;Zilong Tang
中科院分区：
文献类型：
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作者：
Yichao Wan;Yuanhua Li;Chunxing Yan;Jiajun Wen;Zilong Tang
过表达髓细胞白血病序列1（Mcl-1）蛋白是赋予癌细胞对常规抗癌治疗抗性的重要途径。因此，开发Mcl-1抑制剂已成为癌症治疗的有吸引力的策略。本研究设计、合成了一系列新的吲唑-酰基磺酰胺杂合物，并对其作为Mcl-1抑制剂的活性进行了评价。其中，最强的化合物17（Ki= 0.43 μM）显示出比阳性对照AT-101（Ki= 0.45 μM）稍好的对Mcl-1蛋白的抑制活性。令人高兴的是，它显示出超过Bcl-2（Ki= 18 μM）和Bcl-xL（无活性）40倍的选择性。化合物17对PC-3、MDA-MB-231和K562细胞均有较好的抑制活性（IC 50分别为12.3、10.6和6.62 μM），并能有效诱导K562细胞凋亡和caspase-3活化，且呈剂量依赖性。
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 compound17(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, compound17had 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.