Linking Phenotype to Kinase: Identification of a Novel Benzoxaborole Hinge-Binding Motif for Kinase Inhibition and Development of High-Potency Rho Kinase Inhibitors
| Autor: | Liang Liu, Yasheen Zhou, Kurt Jarnagin, Charlotte Virtucio, Xiaoqing Fan, Yong-Kang Zhang, Fernando Rock, Wei Bu, Tsutomu Akama, David C. Sullivan, Yvonne Freund, Chen Dong, Anne Wu |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Boron Compounds
Models Molecular Muscle Relaxation Myocytes Smooth Muscle Aorta Thoracic Blood Pressure Biology Muscle Smooth Vascular Rats Sprague-Dawley Jurkat Cells Structure-Activity Relationship Protein Phosphatase 1 Rats Inbred SHR Animals Humans Structure–activity relationship Kinome Phosphorylation Protein kinase A Protein Kinase Inhibitors Rho-associated protein kinase Pharmacology rho-Associated Kinases Kinase Muscle Smooth Smooth muscle contraction Rats Trachea Biochemistry Cytokines Molecular Medicine Cytokine secretion Muscle Contraction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 347:615-625 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Benzoxaboroles are a novel class of drug-like compounds that have been rich sources of novel inhibitors for various enzymes and of new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the (aminomethylphenoxy)benzoxaborole family, which potently inhibited Toll-like receptor-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 (aminomethylphenoxy)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 cocrystal 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 that may have potential for therapeutic use. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|