Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Eur J Med Chem. 2017 Apr 21;130:195-208. doi: 10.1016/j.ejmech.2017.02.048. Epub 2017 Feb 21.
Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC value of 3.15 μM. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC = 0.33 μM) and 41 (IC = 0.25 μM) were found to protect islet β-cells from apoptosis in dose-dependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes.
死亡相关蛋白激酶相关凋亡诱导激酶 2（DRAK2）是一种丝氨酸/苏氨酸激酶，在多种细胞死亡信号通路中发挥关键作用。抑制 DRAK2 被发现能有效地保护胰岛β细胞免于凋亡，因此 DRAK2 抑制剂是治疗糖尿病的一种很有前途的治疗策略。目前仅发现极少数针对 DRAK2 的化学实体。我们进行了高通量筛选，发现化合物 4 是一种中等强度的 DRAK2 抑制剂，IC 值为 3.15 μM。随后对命中化合物 4 的 SAR 研究导致了新型苯并呋喃-3(2H)-酮系列 DRAK2 抑制剂的开发，这些抑制剂具有更好的效力和针对 26 种选定激酶的有利选择性特征。重要的是，发现最有效的化合物 40（IC=0.33 μM）和 41（IC=0.25 μM）能够以剂量依赖的方式保护胰岛β细胞免于凋亡。这些数据支持这样一种观点，即 DRAK2 的小分子抑制剂是治疗糖尿病的一种很有前途的策略。
