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

Journal Article · Mon May 14 00:00:00 EDT 2012 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm201289r· OSTI ID:1038274

Li, Rongshi; Martin, Mathew P; Liu, Yan; Wang, Binglin; Patel, Ronil A; Zhu, Jin-Yi; Sun, Nan; Pireddu, Roberta; Lawrence, Nicholas J; Li, Jiannong; Haura, Eric B; Sung, Shen-Shu; Guida, Wayne C; Schonbrunn, Ernst; Sebti, Said M ^[1]

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1. Moffitt

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: OTHER
• OSTI ID: 1038274
• Journal Information: J. Med. Chem., Vol. 55, Issue (5) ; 03, 2012; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CRYSTAL STRUCTURE
DESIGN
MAMMARY GLANDS
NEOPLASMS
OPTIMIZATION
PHOSPHORYLATION
PHOSPHOTRANSFERASES
SUBSTRATES