Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
J Med Chem. 2012 Mar 8;55(5):2474-8. doi: 10.1021/jm201289r. Epub 2012 Feb 15.
Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) and ROCK2 (IC(50) = 670 nM), whereas compound 24 was more selective for ROCK2 (IC(50) = 100 nM) over ROCK1 (IC(50) = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.
我们采用高浓度生化分析和基于结构的片段筛选方法，发现了一类新型 Rho 激酶抑制剂。化合物 18 对 ROCK1（IC50=650 nM）和 ROCK2（IC50=670 nM）具有同等抑制活性，而化合物 24 对 ROCK2（IC50=100 nM）的选择性更高，对 ROCK1（IC50=1690 nM）的选择性较低。化合物 18-ROCK1 复合物的晶体结构表明，18 是一种结合在 ATP 结合位点铰链区的 1 型抑制剂。化合物 18 和 24 可有效抑制完整的人乳腺癌细胞中 ROCK 底物 MLC2 的磷酸化。
