4l6q | pdb_00004l6q
ROCK2 in complex with benzoxaborole
Structural highlights
FunctionROCK2_HUMAN Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedBenzoxaboroles are a novel class of drug-like compounds which have been rich sources of novel inhibitors for various enzymes and new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the aminomethyl-phenoxy-benzoxaborole family, which potently inhibited TLR-stimulated cytokine secretion from leukocytes. After considering their structure activity relationships and the central role of kinases in leukocyte biology, we performed a kinome wide screen to investigate the members of the aminomethyl-phenoxy-benzoxaborole family. This technique identified Rho-activated kinase (ROCK) as a target. We showed competitive behavior with respect to ATP, and then determined the ROCK2-drug co-crystal structure. The drug occupies the ATP site, in which the oxaborole moiety provides hydrogen bond donors and acceptors to the hinge, and the aminomethyl group interacts with the magnesium/ATP-interacting aspartic acid common to protein kinases. The series exhibits excellent selectivity against most of the kinome, with greater than 15-fold selectivity against the next best member of the AGC protein kinase subfamily. Medicinal chemistry efforts with structure-based design resulted in a compound with a Ki of 170 nM. Cellular studies revealed strong enzyme inhibition rank correlation with suppression of intracellular phosphorylation of a ROCK substrate. The biochemical potencies of these compounds also translated to functional activity, causing smooth muscle relaxation in rat aorta and guinea pig trachea. The series exhibited oral availability and one member reduced rat blood pressure, consistent with ROCK's role in smooth muscle contraction. Thus, the benzoxaborole moiety represents a novel hinge-binding kinase scaffold which may have potential for therapeutic use. Linking Phenotype to Kinase: Identification of a Novel Benzoxaborole Hinge Binding Motif for Kinase Inhibition and the Development of High Potency Rho-Kinase Inhibitors.,Akama T, Dong C, Virtucio C, Sullivan D, Zhou Y, Zhang YK, Rock F, Freund Y, Bu W, Wu A, Liu L, Fan XQ, Jarnagin K J Pharmacol Exp Ther. 2013 Sep 18. PMID:24049062[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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