Fragment-Based and Structure-Guided Discovery and Optimization of Rho Kinase Inhibitors

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• 作者：Rongshi Li ; Mathew P. Martin ; Yan Liu ; Binglin Wang ; Ronil A. Patel ; Jin-Yi Zhu ; Nan Sun ; Roberta Pireddu ; Nicholas J. Lawrence ; Jiannong Li ; Eric B. Haura ; Shen-Shu Sung ; Wayne C. Guida ; Ernst Schonbrunn ; Said M. Sebti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2474-2478
• 全文大小：257K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

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 (IC₅₀ = 650 nM) and ROCK2 (IC₅₀ = 670 nM), whereas compound 24 was more selective for ROCK2 (IC₅₀ = 100 nM) over ROCK1 (IC₅₀ = 1690 nM). The crystal structure of the compound 18鈥揜OCK1 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.