Larson Gary, Yan Shunqi, Chen Huanming, Rong Frank, Hong Zhi, Wu Jim Zhen
Drug Discovery, Valeant Pharmaceutical Research and Development 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
Bioorg Med Chem Lett. 2007 Jan 1;17(1):172-5. doi: 10.1016/j.bmcl.2006.09.067. Epub 2006 Oct 10.
A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K(i) values as low as 11 nM for Chk2. Computer modeling studies were employed to comprehend the mechanism of action and SAR of these compounds.
合成了一系列异噻唑甲脒化合物，并发现它们是Chk2的新型选择性抑制剂。它们对相关的Chk1激酶无活性。对该骨架进行了构效关系研究，酶动力学分析表明它们是简单的ATP竞争性抑制剂，对Chk2的K(i)值低至11 nM。采用计算机模拟研究来理解这些化合物的作用机制和构效关系。
