| 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 PubMed
Co-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
- ↑ Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol. 1999 Nov 29;147(5):1023-38. PMID:10579722
- ↑ Sebbagh M, Hamelin J, Bertoglio J, Solary E, Breard J. Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med. 2005 Feb 7;201(3):465-71. PMID:15699075 doi:10.1084/jem.20031877
- ↑ Tanaka T, Nishimura D, Wu RC, Amano M, Iso T, Kedes L, Nishida H, Kaibuchi K, Hamamori Y. Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase. J Biol Chem. 2006 Jun 2;281(22):15320-9. Epub 2006 Mar 30. PMID:16574662 doi:10.1074/jbc.M510954200
- ↑ Ma Z, Kanai M, Kawamura K, Kaibuchi K, Ye K, Fukasawa K. Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome duplication. Mol Cell Biol. 2006 Dec;26(23):9016-34. Epub 2006 Oct 2. PMID:17015463 doi:10.1128/MCB.01383-06
- ↑ Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009 Feb 27;104(4):531-40. doi: 10.1161/CIRCRESAHA.108.188524. Epub, 2009 Jan 8. PMID:19131646 doi:10.1161/CIRCRESAHA.108.188524
- ↑ Lock FE, Hotchin NA. Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One. 2009 Dec 4;4(12):e8190. doi: 10.1371/journal.pone.0008190. PMID:19997641 doi:10.1371/journal.pone.0008190
- ↑ Wang HF, Takenaka K, Nakanishi A, Miki Y. BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. Cancer Res. 2011 Jan 1;71(1):68-77. doi: 10.1158/0008-5472.CAN-10-0030. Epub 2010, Nov 16. PMID:21084279 doi:10.1158/0008-5472.CAN-10-0030
- ↑ Herskowitz JH, Seyfried NT, Gearing M, Kahn RA, Peng J, Levey AI, Lah JJ. Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA alters amyloid-beta production. J Biol Chem. 2011 Feb 25;286(8):6117-27. doi: 10.1074/jbc.M110.167239. Epub 2010 , Dec 8. PMID:21147781 doi:10.1074/jbc.M110.167239
- ↑ 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. Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure Based Drug Design. J Med Chem. 2018 Nov 1. doi: 10.1021/acs.jmedchem.8b01098. PMID:30384606 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01098
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