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6ed6
From Proteopedia
Crystal structure of Rock2 with a pyridinylbenzamide based inhibitor
Structural highlights
Function[ROCK2_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 PubMedCo-crystal structures of an early lead compound were obtained in PKA, ROCK1 and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. Aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, were targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Finally, compound 16, a potent and selective pan ROCK inhibitor, was shown to be efficacious in the retinal nerve fiber layer model after oral dosing. Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure Based Drug Design.,Hobson AD, Judge RA, Aguirre AL, Brown BS, Cui Y, Ding P, Dominguez E, DiGiammarino E, Egan DA, Freiberg GM, Gopalakrishnan SM, Harris CM, Honore MP, Kage KL, Kapecki NJ, Ling C, Ma J, Mack H, Mamo M, Maurus S, McRae B, Moore NS, Mueller BK, Mueller R, Namovic MT, Patel K, Pratt SD, Putman CB, Queeney KL, Sarris KK, Schaffter LM, Stoll VS, Vasudevan A, Wang L, Wang L, Wirthl W, Yach K J Med Chem. 2018 Nov 1. doi: 10.1021/acs.jmedchem.8b01098. PMID:30384606[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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