2esm › Citations

The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.

Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J
J Biol Chem 281 260-8 (2006)
Related entries: 2erz, 2etk, 2etr, 3d9v

Cited: 142 times
EuropePMC logo PMID: 16249185

Abstract

ROCK or Rho-associated kinase, a serine/threonine kinase, is an effector of Rho-dependent signaling and is involved in actin-cytoskeleton assembly and cell motility and contraction. The ROCK protein consists of several domains: an N-terminal region, a kinase catalytic domain, a coiled-coil domain containing a RhoA binding site, and a pleckstrin homology domain. The C-terminal region of ROCK binds to and inhibits the kinase catalytic domains, and this inhibition is reversed by binding RhoA, a small GTPase. Here we present the structure of the N-terminal region and the kinase domain. In our structure, two N-terminal regions interact to form a dimerization domain linking two kinase domains together. This spatial arrangement presents the kinase active sites and regulatory sequences on a common face affording the possibility of both kinases simultaneously interacting with a dimeric inhibitory domain or with a dimeric substrate. The kinase domain adopts a catalytically competent conformation; however, no phosphorylation of active site residues is observed in the structure. We also determined the structures of ROCK bound to four different ATP-competitive small molecule inhibitors (Y-27632, fasudil, hydroxyfasudil, and H-1152P). Each of these compounds binds with reduced affinity to cAMP-dependent kinase (PKA), a highly homologous kinase. Subtle differences exist between the ROCK- and PKA-bound conformations of the inhibitors that suggest that interactions with a single amino acid of the active site (Ala215 in ROCK and Thr183 in PKA) determine the relative selectivity of these compounds. Hydroxyfasudil, a metabolite of fasudil, may be selective for ROCK over PKA through a reversed binding orientation.

Reviews - 2esm mentioned but not cited (4)

  1. Approaches of targeting Rho GTPases in cancer drug discovery. Lin Y, Zheng Y. Expert Opin Drug Discov 10 991-1010 (2015)
  2. Rho-Associated Coiled-Coil Kinase (ROCK) in Molecular Regulation of Angiogenesis. Liu J, Wada Y, Katsura M, Tozawa H, Erwin N, Kapron CM, Bao G, Liu J. Theranostics 8 6053-6069 (2018)
  3. Deep Learning in Virtual Screening: Recent Applications and Developments. Kimber TB, Chen Y, Volkamer A. Int J Mol Sci 22 4435 (2021)
  4. Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores. Gógl G, Kornev AP, Reményi A, Taylor SS. Trends Biochem Sci 44 300-311 (2019)

Articles - 2esm mentioned but not cited (12)

  1. A helix scaffold for the assembly of active protein kinases. Kornev AP, Taylor SS, Ten Eyck LF. Proc Natl Acad Sci U S A 105 14377-14382 (2008)
  2. Evaluating caveolin interactions: do proteins interact with the caveolin scaffolding domain through a widespread aromatic residue-rich motif? Byrne DP, Dart C, Rigden DJ. PLoS One 7 e44879 (2012)
  3. Cross-phosphorylation between Arabidopsis thaliana sucrose nonfermenting 1-related protein kinase 1 (AtSnRK1) and its activating kinase (AtSnAK) determines their catalytic activities. Crozet P, Jammes F, Valot B, Ambard-Bretteville F, Nessler S, Hodges M, Vidal J, Thomas M. J Biol Chem 285 12071-12077 (2010)
  4. A chimeric mechanism for polyvalent trans-phosphorylation of PKA by PDK1. Romano RA, Kannan N, Kornev AP, Allison CJ, Taylor SS. Protein Sci 18 1486-1497 (2009)
  5. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. Kast R, Schirok H, Figueroa-Pérez S, Mittendorf J, Gnoth MJ, Apeler H, Lenz J, Franz JK, Knorr A, Hütter J, Lobell M, Zimmermann K, Münter K, Augstein KH, Ehmke H, Stasch JP. Br J Pharmacol 152 1070-1080 (2007)
  6. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. Li R, Martin MP, Liu Y, Wang B, Patel RA, Zhu JY, Sun N, Pireddu R, Lawrence NJ, Li J, Haura EB, Sung SS, Guida WC, Schonbrunn E, Sebti SM. J Med Chem 55 2474-2478 (2012)
  7. Structure of dystrophia myotonica protein kinase. Elkins JM, Amos A, Niesen FH, Pike AC, Fedorov O, Knapp S. Protein Sci 18 782-791 (2009)
  8. Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays. Shen M, Tian S, Pan P, Sun H, Li D, Li Y, Zhou H, Li C, Lee SM, Hou T. Sci Rep 5 16749 (2015)
  9. Prediction of specificity-determining residues for small-molecule kinase inhibitors. Caffrey DR, Lunney EA, Moshinsky DJ. BMC Bioinformatics 9 491 (2008)
  10. Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors. Oliveira RG, Guerra FS, Mermelstein CDS, Fernandes PD, Bastos ITS, Costa FN, Barroso RCR, Ferreira FF, Fraga CAM. J Enzyme Inhib Med Chem 33 1181-1193 (2018)
  11. Dasabuvir suppresses esophageal squamous cell carcinoma growth in vitro and in vivo through targeting ROCK1. Liu X, Jiang Y, Zhou H, Zhao X, Li M, Bao Z, Wang Z, Zhang C, Xie Z, Zhao J, Dong Z, Liu K, Guo Z. Cell Death Dis 14 118 (2023)
  12. Exploring New Therapeutic Avenues for Ophthalmic Disorders: Glaucoma-Related Molecular Docking Evaluation and Bibliometric Analysis for Improved Management of Ocular Diseases. Bodea F, Bungau SG, Negru AP, Radu A, Tarce AG, Tit DM, Bungau AF, Bustea C, Behl T, Radu AF. Bioengineering (Basel) 10 983 (2023)


Reviews citing this publication (29)

  1. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Amano M, Nakayama M, Kaibuchi K. Cytoskeleton (Hoboken) 67 545-554 (2010)
  2. Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions. Julian L, Olson MF. Small GTPases 5 e29846 (2014)
  3. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. Rath N, Olson MF. EMBO Rep 13 900-908 (2012)
  4. Protein kinase inhibitors: contributions from structure to clinical compounds. Johnson LN. Q Rev Biophys 42 1-40 (2009)
  5. The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease. Hartmann S, Ridley AJ, Lutz S. Front Pharmacol 6 276 (2015)
  6. Rho-associated coiled-coil kinase (ROCK) signaling and disease. Schofield AV, Bernard O. Crit Rev Biochem Mol Biol 48 301-316 (2013)
  7. Novel Insights into the Roles of Rho Kinase in Cancer. Wei L, Surma M, Shi S, Lambert-Cheatham N, Shi J. Arch Immunol Ther Exp (Warsz) 64 259-278 (2016)
  8. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. Shi J, Wei L. J Cardiovasc Pharmacol 62 341-354 (2013)
  9. AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. Arencibia JM, Pastor-Flores D, Bauer AF, Schulze JO, Biondi RM. Biochim Biophys Acta 1834 1302-1321 (2013)
  10. Regulation of ROCK activity in cancer. Morgan-Fisher M, Wewer UM, Yoneda A. J Histochem Cytochem 61 185-198 (2013)
  11. AGC kinases, mechanisms of regulation ‎and innovative drug development. Leroux AE, Schulze JO, Biondi RM. Semin Cancer Biol 48 1-17 (2018)
  12. Lining the pockets of kinases and phosphatases. Gold MG, Barford D, Komander D. Curr Opin Struct Biol 16 693-701 (2006)
  13. Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease. Liu Z, Khalil RA. Biochem Pharmacol 153 91-122 (2018)
  14. The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer. Unbekandt M, Olson MF. J Mol Med (Berl) 92 217-225 (2014)
  15. Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), the ROCK-like effectors of Cdc42 and Rac1. Zhao Z, Manser E. Small GTPases 6 81-88 (2015)
  16. RhoGTPases and Rho-effectors in hepatocellular carcinoma metastasis: ROCK N'Rho move it. Wong CC, Wong CM, Au SL, Ng IO. Liver Int 30 642-656 (2010)
  17. Novel inhibitors of AKT: assessment of a different approach targeting the pleckstrin homology domain. Meuillet EJ. Curr Med Chem 18 2727-2742 (2011)
  18. Molecular basis for small molecule inhibition of G protein-coupled receptor kinases. Homan KT, Tesmer JJ. ACS Chem Biol 10 246-256 (2015)
  19. Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase. Abeysinghe HC, Phillips EL, Chin-Cheng H, Beart PM, Roulston CL. Int J Mol Sci 17 288 (2016)
  20. Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions. Donegan RK, Lieberman RL. J Med Chem 59 788-809 (2016)
  21. ROCK as a therapeutic target for ischemic stroke. Sladojevic N, Yu B, Liao JK. Expert Rev Neurother 17 1167-1177 (2017)
  22. New trends in glaucoma risk, diagnosis & management. Kersey T, Clement CI, Bloom P, Cordeiro MF. Indian J Med Res 137 659-668 (2013)
  23. Structure-based drug discovery and protein targets in the CNS. Hubbard RE. Neuropharmacology 60 7-23 (2011)
  24. Discovery of novel inhibitors for the treatment of glaucoma. Cholkar K, Trinh HM, Pal D, Mitra AK. Expert Opin Drug Discov 10 293-313 (2015)
  25. Made to measure - keeping Rho kinase at a distance. Truebestein L, Elsner DJ, Leonard TA. Small GTPases 7 82-92 (2016)
  26. Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk. Qin K, Yu M, Fan J, Wang H, Zhao P, Zhao G, Zeng W, Chen C, Wang Y, Wang A, Schwartz Z, Hong J, Song L, Wagstaff W, Haydon RC, Luu HH, Ho SH, Strelzow J, Reid RR, He TC, Shi LL. Genes Dis 11 103-134 (2024)
  27. Effect of the Rho-Kinase/ROCK Signaling Pathway on Cytoskeleton Components. Guan G, Cannon RD, Coates DE, Mei L. Genes (Basel) 14 272 (2023)
  28. Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics. Ruscetta VM, Seaton TJ, Shakeel A, Vasconcelos SNS, Viirre RD, Adler MJ, Olson MF. Cells 12 534 (2023)
  29. The Magic Methyl and Its Tricks in Drug Discovery and Development. Pinheiro PSM, Franco LS, Fraga CAM. Pharmaceuticals (Basel) 16 1157 (2023)

Articles citing this publication (97)

  1. Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor. Chapman S, Liu X, Meyers C, Schlegel R, McBride AA. J Clin Invest 120 2619-2626 (2010)
  2. Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Nichols RJ, Dzamko N, Hutti JE, Cantley LC, Deak M, Moran J, Bamborough P, Reith AD, Alessi DR. Biochem J 424 47-60 (2009)
  3. Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells. Gilkes DM, Xiang L, Lee SJ, Chaturvedi P, Hubbi ME, Wirtz D, Semenza GL. Proc Natl Acad Sci U S A 111 E384-93 (2014)
  4. Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Hindie V, Stroba A, Zhang H, Lopez-Garcia LA, Idrissova L, Zeuzem S, Hirschberg D, Schaeffer F, Jørgensen TJ, Engel M, Alzari PM, Biondi RM. Nat Chem Biol 5 758-764 (2009)
  5. Specificity of interactions between mDia isoforms and Rho proteins. Lammers M, Meyer S, Kühlmann D, Wittinghofer A. J Biol Chem 283 35236-35246 (2008)
  6. Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. Lock FE, Hotchin NA. PLoS One 4 e8190 (2009)
  7. Activating ROCK1 somatic mutations in human cancer. Lochhead PA, Wickman G, Mezna M, Olson MF. Oncogene 29 2591-2598 (2010)
  8. Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL. Mali RS, Ramdas B, Ma P, Shi J, Munugalavadla V, Sims E, Wei L, Vemula S, Nabinger SC, Goodwin CB, Chan RJ, Traina F, Visconte V, Tiu RV, Lewis TA, Stern AM, Wen Q, Crispino JD, Boswell HS, Kapur R. Cancer Cell 20 357-369 (2011)
  9. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Kubo T, Yamaguchi A, Iwata N, Yamashita T. Ther Clin Risk Manag 4 605-615 (2008)
  10. Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis. Huang D, Zhou T, Lafleur K, Nevado C, Caflisch A. Bioinformatics 26 198-204 (2010)
  11. NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction. Zhang C, Wang HJ, Bao QC, Wang L, Guo TK, Chen WL, Xu LL, Zhou HS, Bian JL, Yang YR, Sun HP, Xu XL, You QD. Oncotarget 7 73593-73606 (2016)
  12. Novel ocular antihypertensive compounds in clinical trials. Chen J, Runyan SA, Robinson MR. Clin Ophthalmol 5 667-677 (2011)
  13. Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations. Gilsbach BK, Ho FY, Vetter IR, van Haastert PJ, Wittinghofer A, Kortholt A. Proc Natl Acad Sci U S A 109 10322-10327 (2012)
  14. Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8, and CDK11. Cee VJ, Chen DY, Lee MR, Nicolaou KC. Angew Chem Int Ed Engl 48 8952-8957 (2009)
  15. Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Li H, Bielas SL, Zaki MS, Ismail S, Farfara D, Um K, Rosti RO, Scott EC, Tu S, Chi NC, Gabriel S, Erson-Omay EZ, Ercan-Sencicek AG, Yasuno K, Çağlayan AO, Kaymakçalan H, Ekici B, Bilguvar K, Gunel M, Gleeson JG. Am J Hum Genet 99 501-510 (2016)
  16. Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure. Komander D, Garg R, Wan PT, Ridley AJ, Barford D. EMBO J 27 3175-3185 (2008)
  17. Synthon-based ligand discovery in virtual libraries of over 11 billion compounds. Sadybekov AA, Sadybekov AV, Liu Y, Iliopoulos-Tsoutsouvas C, Huang XP, Pickett J, Houser B, Patel N, Tran NK, Tong F, Zvonok N, Jain MK, Savych O, Radchenko DS, Nikas SP, Petasis NA, Moroz YS, Roth BL, Makriyannis A, Katritch V. Nature 601 452-459 (2022)
  18. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation. Sunami T, Byrne N, Diehl RE, Funabashi K, Hall DL, Ikuta M, Patel SB, Shipman JM, Smith RF, Takahashi I, Zugay-Murphy J, Iwasawa Y, Lumb KJ, Munshi SK, Sharma S. J Biol Chem 285 4587-4594 (2010)
  19. Can MM-PBSA calculations predict the specificities of protein kinase inhibitors? Page CS, Bates PA. J Comput Chem 27 1990-2007 (2006)
  20. Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations. Shen M, Zhou S, Li Y, Pan P, Zhang L, Hou T. Mol Biosyst 9 361-374 (2013)
  21. Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis. Li G, Zhou J, Budhraja A, Hu X, Chen Y, Cheng Q, Liu L, Zhou T, Li P, Liu E, Gao N. Oncotarget 6 1834-1849 (2015)
  22. miR-335-5p inhibits TGF-β1-induced epithelial-mesenchymal transition in non-small cell lung cancer via ROCK1. Du W, Tang H, Lei Z, Zhu J, Zeng Y, Liu Z, Huang JA. Respir Res 20 225 (2019)
  23. A molecular ruler regulates cytoskeletal remodelling by the Rho kinases. Truebestein L, Elsner DJ, Fuchs E, Leonard TA. Nat Commun 6 10029 (2015)
  24. A novel small-molecule MRCK inhibitor blocks cancer cell invasion. Unbekandt M, Croft DR, Crighton D, Mezna M, McArthur D, McConnell P, Schüttelkopf AW, Belshaw S, Pannifer A, Sime M, Bower J, Drysdale M, Olson MF. Cell Commun Signal 12 54 (2014)
  25. Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632. Yamaguchi H, Miwa Y, Kasa M, Kitano K, Amano M, Kaibuchi K, Hakoshima T. J Biochem 140 305-311 (2006)
  26. Discovery of Rho-kinase inhibitors by docking-based virtual screening. Shen M, Yu H, Li Y, Li P, Pan P, Zhou S, Zhang L, Li S, Lee SM, Hou T. Mol Biosyst 9 1511-1521 (2013)
  27. Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation. Prysyazhna O, Burgoyne JR, Scotcher J, Grover S, Kass D, Eaton P. J Biol Chem 291 17427-17436 (2016)
  28. RhoA modulates functional and physical interaction between ROCK1 and Erk1/2 in selenite-induced apoptosis of leukaemia cells. Li F, Jiang Q, Shi KJ, Luo H, Yang Y, Xu CM. Cell Death Dis 4 e708 (2013)
  29. The Structure of an NDR/LATS Kinase-Mob Complex Reveals a Novel Kinase-Coactivator System and Substrate Docking Mechanism. Gógl G, Schneider KD, Yeh BJ, Alam N, Nguyen Ba AN, Moses AM, Hetényi C, Reményi A, Weiss EL. PLoS Biol 13 e1002146 (2015)
  30. Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. Waldschmidt HV, Homan KT, Cruz-Rodríguez O, Cato MC, Waninger-Saroni J, Larimore KM, Cannavo A, Song J, Cheung JY, Kirchhoff PD, Koch WJ, Tesmer JJ, Larsen SD. J Med Chem 59 3793-3807 (2016)
  31. Co-crystal structures of inhibitors with MRCKβ, a key regulator of tumor cell invasion. Heikkila T, Wheatley E, Crighton D, Schroder E, Boakes A, Kaye SJ, Mezna M, Pang L, Rushbrooke M, Turnbull A, Olson MF. PLoS One 6 e24825 (2011)
  32. Phosphorylation and Activation of RhoA by ERK in Response to Epidermal Growth Factor Stimulation. Tong J, Li L, Ballermann B, Wang Z. PLoS One 11 e0147103 (2016)
  33. Crystal structure of a coiled-coil domain from human ROCK I. Tu D, Li Y, Song HK, Toms AV, Gould CJ, Ficarro SB, Marto JA, Goode BL, Eck MJ. PLoS One 6 e18080 (2011)
  34. High-content screening of feeder-free human embryonic stem cells to identify pro-survival small molecules. Andrews PD, Becroft M, Aspegren A, Gilmour J, James MJ, McRae S, Kime R, Allcock RW, Abraham A, Jiang Z, Strehl R, Mountford JC, Milligan G, Houslay MD, Adams DR, Frearson JA. Biochem J 432 21-33 (2010)
  35. Surface-plasmon-resonance-based biosensor with immobilized bisubstrate analog inhibitor for the determination of affinities of ATP- and protein-competitive ligands of cAMP-dependent protein kinase. Viht K, Schweinsberg S, Lust M, Vaasa A, Raidaru G, Lavogina D, Uri A, Herberg FW. Anal Biochem 362 268-277 (2007)
  36. Structure of Shroom domain 2 reveals a three-segmented coiled-coil required for dimerization, Rock binding, and apical constriction. Mohan S, Rizaldy R, Das D, Bauer RJ, Heroux A, Trakselis MA, Hildebrand JD, VanDemark AP. Mol Biol Cell 23 2131-2142 (2012)
  37. Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine. Waldschmidt HV, Homan KT, Cato MC, Cruz-Rodríguez O, Cannavo A, Wilson MW, Song J, Cheung JY, Koch WJ, Tesmer JJ, Larsen SD. J Med Chem 60 3052-3069 (2017)
  38. Conserved modular domains team up to latch-open active protein kinase Cα. Swanson CJ, Ritt M, Wang W, Lang MJ, Narayan A, Tesmer JJ, Westfall M, Sivaramakrishnan S. J Biol Chem 289 17812-17829 (2014)
  39. Discovery of a benzofuran derivative (MBPTA) as a novel ROCK inhibitor that protects against MPP⁺-induced oxidative stress and cell death in SH-SY5Y cells. Chong CM, Shen M, Zhou ZY, Pan P, Hoi PM, Li S, Liang W, Ai N, Zhang LQ, Li CW, Yu H, Hou T, Lee SM. Free Radic Biol Med 74 283-293 (2014)
  40. Inhibition of Rho-Associated Kinase 1/2 Attenuates Tumor Growth in Murine Gastric Cancer. Hinsenkamp I, Schulz S, Roscher M, Suhr AM, Meyer B, Munteanu B, Fuchser J, Schoenberg SO, Ebert MP, Wängler B, Hopf C, Burgermeister E. Neoplasia 18 500-511 (2016)
  41. Rho kinase activation and gene expression related to vascular remodeling in normotensive rats with high angiotensin I converting enzyme levels. Rivera P, Ocaranza MP, Lavandero S, Jalil JE. Hypertension 50 792-798 (2007)
  42. Structure-activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of ROCK-II. Feng Y, Cameron MD, Frackowiak B, Griffin E, Lin L, Ruiz C, Schröter T, LoGrasso P. Bioorg Med Chem Lett 17 2355-2360 (2007)
  43. Design and synthesis of rho kinase inhibitors (III). Iwakubo M, Takami A, Okada Y, Kawata T, Tagami Y, Sato M, Sugiyama T, Fukushima K, Taya S, Amano M, Kaibuchi K, Iijima H. Bioorg Med Chem 15 1022-1033 (2007)
  44. Chroman-3-amides as potent Rho kinase inhibitors. Chen YT, Bannister TD, Weiser A, Griffin E, Lin L, Ruiz C, Cameron MD, Schürer S, Duckett D, Schröter T, LoGrasso P, Feng Y. Bioorg Med Chem Lett 18 6406-6409 (2008)
  45. Design and Profiling of a Subcellular Targeted Optogenetic cAMP-Dependent Protein Kinase. O'Banion CP, Priestman MA, Hughes RM, Herring LE, Capuzzi SJ, Lawrence DS. Cell Chem Biol 25 100-109.e8 (2018)
  46. Structural analysis of protein kinase A mutants with Rho-kinase inhibitor specificity. Bonn S, Herrero S, Breitenlechner CB, Erlbruch A, Lehmann W, Engh RA, Gassel M, Bossemeyer D. J Biol Chem 281 24818-24830 (2006)
  47. Linking phenotype to kinase: identification of a novel benzoxaborole hinge-binding motif for kinase inhibition and development of high-potency rho kinase inhibitors. Akama T, Dong C, Virtucio C, Sullivan D, Zhou Y, Zhang YK, Rock F, Freund Y, Liu L, Bu W, Wu A, Fan XQ, Jarnagin K. J Pharmacol Exp Ther 347 615-625 (2013)
  48. Rho kinase inhibitors stimulate the migration of human cultured osteoblastic cells by regulating actomyosin activity. Zhang X, Li C, Gao H, Nabeka H, Shimokawa T, Wakisaka H, Matsuda S, Kobayashi N. Cell Mol Biol Lett 16 279-295 (2011)
  49. Structure of WbdD: a bifunctional kinase and methyltransferase that regulates the chain length of the O antigen in Escherichia coli O9a. Hagelueken G, Huang H, Clarke BR, Lebl T, Whitfield C, Naismith JH. Mol Microbiol 86 730-742 (2012)
  50. A collapsin response mediator protein 2 isoform controls myosin II-mediated cell migration and matrix assembly by trapping ROCK II. Yoneda A, Morgan-Fisher M, Wait R, Couchman JR, Wewer UM. Mol Cell Biol 32 1788-1804 (2012)
  51. KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway. Li H, Jiang X, Yu Y, Huang W, Xing H, Agar NY, Yang HW, Yang B, Carroll RS, Johnson MD. Oncogene 34 1432-1441 (2015)
  52. ROCK1 but not ROCK2 contributes to RhoA signaling and NMIIA-mediated contractility at the epithelial zonula adherens. Priya R, Liang X, Teo JL, Duszyc K, Yap AS, Gomez GA. Mol Biol Cell 28 12-20 (2017)
  53. Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen. Jester BW, Gaj A, Shomin CD, Cox KJ, Ghosh I. J Med Chem 55 1526-1537 (2012)
  54. A practical synthesis of Rho-Kinase inhibitor Y-27632 and fluoro derivatives and their evaluation in human pluripotent stem cells. Paleček J, Zweigerdt R, Olmer R, Martin U, Kirschning A, Dräger G. Org Biomol Chem 9 5503-5510 (2011)
  55. 4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors. Liddle J, Bamborough P, Barker MD, Campos S, Cousins RP, Cutler GJ, Hobbs H, Holmes DS, Ioannou C, Mellor GW, Morse MA, Payne JJ, Pritchard JM, Smith KJ, Tape DT, Whitworth C, Williamson RA. Bioorg Med Chem Lett 19 2504-2508 (2009)
  56. Rho Kinase Inhibition with Fasudil in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis-Symptomatic Treatment Potential after Disease Onset. Günther R, Balck A, Koch JC, Nientiedt T, Sereda M, Bähr M, Lingor P, Tönges L. Front Pharmacol 8 17 (2017)
  57. Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM, Lawrence NJ. Medchemcomm 3 699-709 (2012)
  58. Signal transduction and modulating pathways in tryptamine-evoked vasopressor responses of the rat isolated perfused mesenteric bed. Anwar MA, Ford WR, Herbert AA, Broadley KJ. Vascul Pharmacol 58 140-149 (2013)
  59. Structure of a highly conserved domain of Rock1 required for Shroom-mediated regulation of cell morphology. Mohan S, Das D, Bauer RJ, Heroux A, Zalewski JK, Heber S, Dosunmu-Ogunbi AM, Trakselis MA, Hildebrand JD, Vandemark AP. PLoS One 8 e81075 (2013)
  60. The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat. Pankey EA, Byun RJ, Smith WB, Bhartiya M, Bueno FR, Badejo AM, Stasch JP, Murthy SN, Nossaman BD, Kadowitz PJ. Can J Physiol Pharmacol 90 825-835 (2012)
  61. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Boland S, Defert O, Alen J, Bourin A, Castermans K, Kindt N, Boumans N, Panitti L, Van de Velde S, Stalmans I, Leysen D. Bioorg Med Chem Lett 23 6442-6446 (2013)
  62. Benzothiophene containing Rho kinase inhibitors: Efficacy in an animal model of glaucoma. Davis RL, Kahraman M, Prins TJ, Beaver Y, Cook TG, Cramp J, Cayanan CS, Gardiner EM, McLaughlin MA, Clark AF, Hellberg MR, Shiau AK, Noble SA, Borchardt AJ. Bioorg Med Chem Lett 20 3361-3366 (2010)
  63. Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors. Schirok H, Kast R, Figueroa-Pérez S, Bennabi S, Gnoth MJ, Feurer A, Heckroth H, Thutewohl M, Paulsen H, Knorr A, Hütter J, Lobell M, Münter K, Geiss V, Ehmke H, Lang D, Radtke M, Mittendorf J, Stasch JP. ChemMedChem 3 1893-1904 (2008)
  64. Rho-Associated Kinases and Non-muscle Myosin IIs Inhibit the Differentiation of Human iPSCs to Pancreatic Endoderm. Toyoda T, Kimura A, Tanaka H, Ameku T, Mima A, Hirose Y, Nakamura M, Watanabe A, Osafune K. Stem Cell Reports 9 419-428 (2017)
  65. Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation. El Bakkouri M, Kouidmi I, Wernimont AK, Amani M, Hutchinson A, Loppnau P, Kim JJ, Flueck C, Walker JR, Seitova A, Senisterra G, Kakihara Y, Kim C, Blackman MJ, Calmettes C, Baker DA, Hui R. Proc Natl Acad Sci U S A 116 14164-14173 (2019)
  66. Enzyme kinetics and distinct modulation of the protein kinase N family of kinases by lipid activators and small molecule inhibitors. Falk MD, Liu W, Bolaños B, Unsal-Kacmaz K, Klippel A, Grant S, Brooun A, Timofeevski S. Biosci Rep 34 e00097 (2014)
  67. 7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel ROCK inhibitor blocks cytoskeleton function and cell migration. Tsai CC, Liu HF, Hsu KC, Yang JM, Chen C, Liu KK, Hsu TS, Chao JI. Biochem Pharmacol 81 856-865 (2011)
  68. Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors. Ray P, Wright J, Adam J, Bennett J, Boucharens S, Black D, Cook A, Brown AR, Epemolu O, Fletcher D, Haunso A, Huggett M, Jones P, Laats S, Lyons A, Mestres J, de Man J, Morphy R, Rankovic Z, Sherborne B, Sherry L, van Straten N, Westwood P, Zaman GZ. Bioorg Med Chem Lett 21 97-101 (2011)
  69. Genetic Variants in Caveolin-1 and RhoA/ROCK1 Are Associated with Clear Cell Renal Cell Carcinoma Risk in a Chinese Population. Zhao R, Liu K, Huang Z, Wang J, Pan Y, Huang Y, Deng X, Liu J, Qin C, Cheng G, Hua L, Li J, Yin C. PLoS One 10 e0128771 (2015)
  70. Inhibition of Rho-kinase Attenuates Left Ventricular Remodeling Caused by Chronic Intermittent Hypoxia in Rats via Suppressing Myocardial Inflammation and Apoptosis. Wang ZH, Zhu D, Xie S, Deng Y, Pan Y, Ren J, Liu HG. J Cardiovasc Pharmacol 70 102-109 (2017)
  71. ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance. Hu YB, Zou Y, Huang Y, Zhang YF, Lourenco GF, Chen SD, Halliday GM, Wang G, Ren RJ. Front Cell Neurosci 10 253 (2016)
  72. Dephosphorylation and mitochondrial translocation of cofilin sensitizes human leukemia cells to cerulenin-induced apoptosis via the ROCK1/Akt/JNK signaling pathway. Zhang Y, Fu R, Liu Y, Li J, Zhang H, Hu X, Chen Y, Liu X, Li Y, Li P, Liu E, Gao N. Oncotarget 7 20655-20668 (2016)
  73. Ser1333 phosphorylation indicates ROCKI activation. Chuang HH, Liang SW, Chang ZF, Lee HH. J Biomed Sci 20 83 (2013)
  74. Triazine and pyrimidine based ROCK inhibitors with efficacy in spontaneous hypertensive rat model. Ho KK, Beasley JR, Belanger L, Black D, Chan JH, Dunn D, Hu B, Klon A, Kultgen SG, Ohlmeyer M, Parlato SM, Ray PC, Pham Q, Rong Y, Roughton AL, Walker TL, Wright J, Xu K, Xu Y, Zhang L, Webb M. Bioorg Med Chem Lett 19 6027-6031 (2009)
  75. Actin Dynamics, Regulated by RhoA-LIMK-Cofilin Signaling, Mediates Rod Photoreceptor Axonal Retraction After Retinal Injury. Wang W, Halasz E, Townes-Anderson E. Invest Ophthalmol Vis Sci 60 2274-2285 (2019)
  76. Radiosynthesis of N-[(11)C]-methyl-hydroxyfasudil as a new potential PET radiotracer for rho-kinases (ROCKs). Valdivia AC, Mason S, Collins J, Buckley KR, Coletta P, Beanlands RS, Dasilva JN. Appl Radiat Isot 68 325-328 (2010)
  77. Design, synthesis and biological evaluations of a long-acting, hypoxia-activated prodrug of fasudil, a ROCK inhibitor, to reduce its systemic side-effects. Al-Hilal TA, Hossain MA, Alobaida A, Alam F, Keshavarz A, Nozik-Grayck E, Stenmark KR, German NA, Ahsan F. J Control Release 334 237-247 (2021)
  78. Local delivery of RhoA siRNA by PgP nanocarrier reduces inflammatory response and improves neuronal cell survival in a rat TBI model. Macks C, Jeong D, Lee JS. Nanomedicine 32 102343 (2021)
  79. PAK4 crystal structures suggest unusual kinase conformational movements. Zhang EY, Ha BH, Boggon TJ. Biochim Biophys Acta Proteins Proteom 1866 356-365 (2018)
  80. A Highly Selective Rho-Kinase Inhibitor (ITRI-E-212) Potentially Treats Glaucoma Upon Topical Administration With Low Incidence of Ocular Hyperemia. Hsu CR, Chen YH, Liu CP, Chen CH, Huang KK, Huang JW, Lin MN, Lin CL, Chen WR, Hsu YL, Lee TC, Chou SH, Tu CM, Hwang CS, Huang YC, Lu DW. Invest Ophthalmol Vis Sci 60 624-633 (2019)
  81. Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations. Mei D, Yin Y, Wu F, Cui J, Zhou H, Sun G, Jiang Y, Feng Y. Bioorg Med Chem 23 2505-2517 (2015)
  82. In Silico Investigations of Chemical Constituents of Clerodendrum colebrookianum in the Anti-Hypertensive Drug Targets: ROCK, ACE, and PDE5. Arya H, Syed SB, Singh SS, Ampasala DR, Coumar MS. Interdiscip Sci 10 792-804 (2018)
  83. Comment Angio-associated migratory cell protein and smooth muscle cell migration in development of restenosis and atherosclerosis. Holvoet P, Sinnaeve P. J Am Coll Cardiol 52 312-314 (2008)
  84. Binding of BIS like and other ligands with the GSK-3β kinase: a combined docking and MM-PBSA study. Jena NR. J Mol Model 18 631-644 (2012)
  85. Chemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors. Beroza P, Crawford JJ, Ganichkin O, Gendelev L, Harris SF, Klein R, Miu A, Steinbacher S, Klingler FM, Lemmen C. Nat Commun 13 6447 (2022)
  86. Recent Patents on Emerging Therapeutics for the Treatment of Glaucoma, Age Related Macular Degeneration and Uveitis. Vadlapudi AD, Patel A, Cholkar K, Mitra AK. Recent Pat Biomed Eng 5 83-101 (2012)
  87. Associations between the Rho kinase-1 catalytic and PH domain regulatory unit. Craft JW, Zhang H, Charendoff MN, Mindrebo JT, Schwartz RJ, Briggs JM. J Mol Graph Model 46 74-82 (2013)
  88. Chronic inflammatory demyelinating polyneuropathy sera inhibit axonal growth of mouse dorsal root ganglion neurons by activation of Rho-kinase. Taniguchi J, Sawai S, Mori M, Kubo T, Kanai K, Misawa S, Isose S, Yamashita T, Kuwabara S. Ann Neurol 66 694-697 (2009)
  89. Partial contribution of Rho-kinase inhibition to the bioactivity of Ganoderma lingzhi and its isolated compounds: insights on discovery of natural Rho-kinase inhibitors. Amen Y, Zhu Q, Tran HB, Afifi MS, Halim AF, Ashour A, Ashour A, Shimizu K. J Nat Med 71 380-388 (2017)
  90. Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account. Wu F, Büttner FH, Chen R, Hickey E, Jakes S, Kaplita P, Kashem MA, Kerr S, Kugler S, Paw Z, Prokopowicz A, Shih CK, Snow R, Young E, Cywin CL. Bioorg Med Chem Lett 20 3235-3239 (2010)
  91. Ligand-induced conformational rearrangements regulate the switch between membrane-proximal and distal functions of Rho kinase 2. Hajdú I, Szilágyi A, Végh BM, Wacha A, Györffy D, Gráczer É, Somogyi M, Gál P, Závodszky P. Commun Biol 3 721 (2020)
  92. Rho-kinase inhibition improves haemodynamic responses and circulating ATP during hypoxia and moderate intensity handgrip exercise in healthy older adults. Racine ML, Terwoord JD, Ketelhut NB, Bachman NP, Richards JC, Luckasen GJ, Dinenno FA. J Physiol 600 3265-3285 (2022)
  93. Serum ROCK1 mRNA is of great diagnostic value for glioma patients. Liu Y, Zhang J, Wang D, Yang X. Medicine (Baltimore) 98 e15413 (2019)
  94. Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal-regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment. Zaky YA, Rashad MW, Zaater MA, El Kerdawy AM. BMC Chem 18 2 (2024)
  95. Discovery of vascular Rho kinase (ROCK) inhibitory peptides. Abbasgholizadeh R, Zhang H, Craft JW, Bryan RM, Bark SJ, Briggs JM, Fox RO, Agarkov A, Zimmer WE, Gilbertson SR, Schwartz RJ. Exp Biol Med (Maywood) 244 940-951 (2019)
  96. Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidines as atypical protein kinase C inhibitors to control retinal vascular permeability and cytokine-induced edema. Liu X, Wilson MW, Liu K, Lee P, Yeomans L, Hagen SE, Lin CM, Wen B, Sun D, White AD, Showalter HD, Antonetti DA. Bioorg Med Chem 28 115480 (2020)
  97. The combination approach with Rhokinase inhibition and mechanical circulatory support in myocardial ischemia-reperfusion injury: Rho-kinase inhibition and ventricular unloading. Miyahara S, Jenke A, Yazdanyar M, Kistner J, Immohr MB, Sugimura Y, Aubin H, Kamiya H, Okita Y, Okita Y, Lichtenberg A, Akhyari P. Asian Cardiovasc Thorac Ann 30 894-905 (2022)


Quick links