While examining benzoxaborole activity in phenotype screens, there was evidence that the aminomethyl-phenoxy-benzoxaborale family inhibited Toll-like receptor-stimulated cytokine secretion from leukocytes. A kinome-wide screen was performed to investigate the members of the aminomethyl-phenoxy-benzoxaborole family, identifying Rho-activated kinase (ROCK) as a target. The study showed competitive behavior with respect to ATP and then determined the ROCK2-drug co-crystal structure. The series exhibits excellent selectivity against most of the kinome and medicinal chemistry efforts, with structure-based design resulting in a compound with a Ki of 170 nM. The biochemical potencies of these compounds translated to smooth muscle relaxation and to reduced rat blood pressure, consistent with ROCK pharmacology. Thus, the benzoxaborole moity represents a novel hinge-binding kinase scaffold, which may have potential therapeutic use.
See article at J Pharmacol Exp Ther 2013, 347:615–625.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics