Fragment-Based and Structure-Guided Discovery and Optimization of Rho Kinase Inhibitors
- 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:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- OTHER
- OSTI ID:
- 1038274
- Journal Information:
- J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (5) ; 03, 2012 Vol. 55; ISSN JMCMAR; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- ENGLISH
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