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

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{sub 50} = 650 nM) and ROCK2 (IC{sub 50} = 670 nM), whereas compound 24 was more selective for ROCK2 (IC{sub 50} = 100 nM) over ROCK1 (IC{sub 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.
Authors:
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  1. (Moffitt)
Publication Date:
OSTI Identifier:
1038274
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Med. Chem.; Journal Volume: 55; Journal Issue: (5) ; 03, 2012
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
OTHER
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; DESIGN; MAMMARY GLANDS; NEOPLASMS; OPTIMIZATION; PHOSPHORYLATION; PHOSPHOTRANSFERASES; SUBSTRATES