Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors

  • J Med Chem. 2012 Mar 8;55(5):2474-8. doi: 10.1021/jm201289r.
Rongshi Li  1 ,  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
Affiliations
  • 1. Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA. [email protected]
PMID: 22272748 DOI: 10.1021/jm201289r
Abstract

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.