Fragment-Based and Structure-Guided Discovery and Optimization of Rho Kinase Inhibitors
Copyright policy )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(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.
- University of South Florida United States
- Moffitt Cancer Center United States
Mitogen-Activated Protein Kinase 1, Models, Molecular, rho-Associated Kinases, Binding Sites, Mitogen-Activated Protein Kinase 3, Myosin Light Chains, Molecular Structure, Crystallography, X-Ray, Structure-Activity Relationship, Adenosine Triphosphate, Cell Line, Tumor, Humans, Phosphorylation, Cardiac Myosins
Mitogen-Activated Protein Kinase 1, Models, Molecular, rho-Associated Kinases, Binding Sites, Mitogen-Activated Protein Kinase 3, Myosin Light Chains, Molecular Structure, Crystallography, X-Ray, Structure-Activity Relationship, Adenosine Triphosphate, Cell Line, Tumor, Humans, Phosphorylation, Cardiac Myosins
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