3v8s › Citations

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 2474-8 (2012)
Cited: 25 times
EuropePMC logo PMID: 22272748

Abstract

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) and ROCK2 (IC(50) = 670 nM), whereas compound 24 was more selective for ROCK2 (IC(50) = 100 nM) over ROCK1 (IC(50) = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

Articles - 3v8s mentioned but not cited (9)

  1. Identification and structure-function analysis of subfamily selective G protein-coupled receptor kinase inhibitors. Homan KT, Larimore KM, Elkins JM, Szklarz M, Knapp S, Tesmer JJ. ACS Chem Biol 10 310-319 (2015)
  2. 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)
  3. 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)
  4. FRAGSITE: A Fragment-Based Approach for Virtual Ligand Screening. Zhou H, Cao H, Skolnick J. J Chem Inf Model 61 2074-2089 (2021)
  5. 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)
  6. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  7. Identification of afzelin potential targets in inhibiting triple-negative breast cancer cell migration using reverse docking. Rachmi E, Purnomo BB, Endharti AT, Fitri LE. Porto Biomed J 5 e095 (2020)
  8. In Vitro and In Silico Investigation of BCI Anticancer Properties and Its Potential for Chemotherapy-Combined Treatments. Marciniak B, Kciuk M, Mujwar S, Sundaraj R, Bukowski K, Gruszka R. Cancers (Basel) 15 4442 (2023)
  9. Integrated network pharmacology, bioinformatics, and molecular docking to explore the mechanisms of berberine regulating autophagy in breast cancer. Huang B, Wen G, Li R, Wu M, Zou Z. Medicine (Baltimore) 102 e35070 (2023)


Reviews citing this publication (10)

  1. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. Rath N, Olson MF. EMBO Rep 13 900-908 (2012)
  2. 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)
  3. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. Shi J, Wei L. J Cardiovasc Pharmacol 62 341-354 (2013)
  4. Approaches of targeting Rho GTPases in cancer drug discovery. Lin Y, Zheng Y. Expert Opin Drug Discov 10 991-1010 (2015)
  5. Molecular basis for small molecule inhibition of G protein-coupled receptor kinases. Homan KT, Tesmer JJ. ACS Chem Biol 10 246-256 (2015)
  6. Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities. Chin VT, Nagrial AM, Chou A, Biankin AV, Gill AJ, Timpson P, Pajic M. Expert Rev Mol Med 17 e17 (2015)
  7. Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions. Donegan RK, Lieberman RL. J Med Chem 59 788-809 (2016)
  8. Rho kinase inhibitors: a patent review (2012 - 2013). Feng Y, LoGrasso PV. Expert Opin Ther Pat 24 295-307 (2014)
  9. Protein crystallography and fragment-based drug design. Caliandro R, Belviso DB, Aresta BM, de Candia M, Altomare CD. Future Med Chem 5 1121-1140 (2013)
  10. Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease. Benn CL, Dawson LA. Front Aging Neurosci 12 242 (2020)

Articles citing this publication (6)

  1. Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Patel RA, Liu Y, Wang B, Li R, Sebti SM. Oncogene 33 550-555 (2014)
  2. 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)
  3. Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors. Gavara L, Suchaud V, Nauton L, Théry V, Anizon F, Moreau P. Bioorg Med Chem Lett 23 2298-2301 (2013)
  4. A Family of Heterobimetallic Cubes Shows Spin-Crossover Behaviour Near Room Temperature. Hardy M, Tessarolo J, Holstein JJ, Struch N, Wagner N, Weisbarth R, Engeser M, Beck J, Horiuchi S, Clever GH, Lützen A. Angew Chem Int Ed Engl 60 22562-22569 (2021)
  5. Discovery of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines as potent PIM inhibitors. Wu B, Wang HL, Cee VJ, Lanman BA, Nixey T, Pettus L, Reed AB, Wurz RP, Guerrero N, Sastri C, Winston J, Lipford JR, Lee MR, Mohr C, Andrews KL, Tasker AS. Bioorg Med Chem Lett 25 775-780 (2015)
  6. Fine tuning through valence bond tautomerization of ancillary ligands in ruthenium(ii) arene complexes for better anticancer activity and enzyme inhibition properties. Mandal P, Malviya N, Guedes da Silva MF, Dhankhar SS, Nagaraja CM, Mobin SM, Mukhopadhyay S. Dalton Trans 45 19277-19289 (2016)


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