Rho associated coiled-coil containing protein kinase 2 | Rho kinase | IUPHAR Guide to IMMUNOPHARMACOLOGY

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Rho associated coiled-coil containing protein kinase 2

  Target has curated data in GtoImmuPdb

Target id: 1504

Nomenclature: Rho associated coiled-coil containing protein kinase 2

Abbreviated Name: Rho kinase 2

Systematic Nomenclature: ROCK2

Family: Rho kinase

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1388 2p24 ROCK2 Rho associated coiled-coil containing protein kinase 2
Mouse - 1388 12 A3 Rock2 Rho-associated coiled-coil containing protein kinase 2
Rat - 1388 6q15-q16 Rock2 Rho-associated coiled-coil containing protein kinase 2
Previous and Unofficial Names
p150 ROK-alpha | p164 ROCK-2 | RhoA - binding serine/threosine kinase alpha (ROK - alpha) | rho-associated protein kinase 2 | ROCK-II | ROKalpha | Rock2m | Rho-associated, coiled-coil containing protein kinase 2
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
cortistatin A Hs Inhibition 6.7 pKd 4
pKd 6.7 (Kd 2.2x10-7 M) [4]
netarsudil Hs Inhibition 8.7 pKi 13
pKi 8.7 (Ki 2x10-9 M) [13]
SAR407899 Hs Inhibition 7.4 pKi 10
pKi 7.4 (Ki 3.6x10-8 M) [10]
SAR407899 Rn Inhibition 7.4 pKi 10
pKi 7.4 (Ki 4.1x10-8 M) [10]
Y27632 Hs Inhibition 6.8 – 6.9 pKi 10,15
pKi 6.8 – 6.9 (Ki 1.4x10-7 – 1.14x10-7 M) [10,15]
fasudil Hs Inhibition 6.6 pKi 10
pKi 6.6 (Ki 2.71x10-7 M) [10]
RKI-1447 Hs Inhibition >9.0 pIC50 11
pIC50 >9.0 (IC50 <1x10-9 M) [11]
compound 11d [DOI: 10.1039/c0md00194e] Hs Inhibition >9.0 pIC50 5
pIC50 >9.0 (IC50 <1x10-9 M) [5]
compound 35 [PMID: 20684608] Hs Inhibition >9.0 pIC50 8
pIC50 >9.0 (IC50 <1x10-9 M) [8]
GSK269962A Hs Inhibition 8.4 pIC50 7
pIC50 8.4 (IC50 4x10-9 M) [7]
Description: In vitro inhibitory activity against recombinant ROCK2.
compound 32 [PMID: 20471253] Hs Inhibition 8.4 pIC50 3
pIC50 8.4 (IC50 4x10-9 M) [3]
Rho kinase inhibitor IV Hs Inhibition 7.9 pIC50 14
pIC50 7.9 (IC50 1.18x10-8 M) [14]
compound 22 [PMID: 20462760] Hs Inhibition 7.7 pIC50 18
pIC50 7.7 (IC50 1.9x10-8 M) [18]
SAR407899 Hs Inhibition 7.0 pIC50 10
pIC50 7.0 (IC50 1.02x10-7 M) [10]
KD025 Hs Inhibition 7.0 pIC50 2
pIC50 7.0 (IC50 1.05x10-7 M) [2]
Description: In a radiometric cell-free enzyme assay.
Y27632 Hs Inhibition 6.3 – 7.2 pIC50 10,18
pIC50 6.3 – 7.2 (IC50 4.87x10-7 – 6.1x10-8 M) [10,18]
fasudil Hs Inhibition 5.9 – 5.9 pIC50 10,12
pIC50 5.9 – 5.9 (IC50 1.349x10-6 – 1.29x10-6 M) [10,12]
verosudil Hs Inhibition - - 16
[16]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 6,17

Key to terms and symbols Click column headers to sort
Target used in screen: ROCK2
Ligand Sp. Type Action Value Parameter
staurosporine Hs Inhibitor Inhibition 9.6 pKd
ruxolitinib Hs Inhibitor Inhibition 7.3 pKd
lestaurtinib Hs Inhibitor Inhibition 7.2 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.9 pKd
sunitinib Hs Inhibitor Inhibition 6.8 pKd
GSK690693 Hs Inhibitor Inhibition 6.7 pKd
KW-2449 Hs Inhibitor Inhibition 6.6 pKd
bosutinib Hs Inhibitor Inhibition 6.4 pKd
AST-487 Hs Inhibitor Inhibition 6.4 pKd
tofacitinib Hs Inhibitor Inhibition 6.4 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,9

Key to terms and symbols Click column headers to sort
Target used in screen: ROCK-II/ROCK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 0.7 1.0 0.0
Rho kinase inhibitor IV Hs Inhibitor Inhibition 3.2 1.0 -1.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 6.2 0.0 1.0
PKR inhibitor Hs Inhibitor Inhibition 11.7 5.0 1.0
H-89 Hs Inhibitor Inhibition 15.4 8.0 0.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 17.3 10.0 1.0
K-252a Hs Inhibitor Inhibition 18.5 15.0 2.0
JNJ-7706621 Hs Inhibitor Inhibition 18.6 16.0 3.0
Y27632 Hs Inhibitor Inhibition 26.3 19.0 4.0
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 28.6 8.0 7.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
ROCK2 plays a role in controlling T-cell plasticity and macrophage polarization, skewing polarization towards M1-type macrophages [19]. ROCK2-selective inhibitors have been shown to reduce clinical manifestations in experimental models of autoimmunity and chronic graft-vs.-host disease, and are in clinical development for the treatment of several inflammatory disorders.
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0032723 positive regulation of connective tissue growth factor production ISS
GO:0090271 positive regulation of fibroblast growth factor production ISS

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Boerma M, Fu Q, Wang J, Loose DS, Bartolozzi A, Ellis JL, McGonigle S, Paradise E, Sweetnam P, Fink LM et al.. (2008) Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin. Blood Coagul. Fibrinolysis, 19 (7): 709-18. [PMID:18832915]

3. Bosanac T, Hickey ER, Ginn J, Kashem M, Kerr S, Kugler S, Li X, Olague A, Schlyer S, Young ER. (2010) Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines. Bioorg. Med. Chem. Lett., 20 (12): 3746-9. [PMID:20471253]

4. Cee VJ, Chen DY, Lee MR, Nicolaou KC. (2009) Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8, and CDK11. Angew. Chem. Int. Ed. Engl., 48 (47): 8952-7. [PMID:19844931]

5. Chen YT, Vojkovsky T, Fang X, Pocas JR, Grant W, Handy AMW, Schroter T, LoGrasso P, Bannister TD, Feng Y. (2011) Asymmetric synthesis of potent chroman-based Rho kinase (ROCK-II) inhibitors. Med Chem Commun, 2: 73-75.

6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

7. Doe C, Bentley R, Behm DJ, Lafferty R, Stavenger R, Jung D, Bamford M, Panchal T, Grygielko E, Wright LL et al.. (2007) Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J. Pharmacol. Exp. Ther., 320 (1): 89-98. [PMID:17018693]

8. Fang X, Yin Y, Chen YT, Yao L, Wang B, Cameron MD, Lin L, Khan S, Ruiz C, Schröter T et al.. (2010) Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J. Med. Chem., 53 (15): 5727-37. [PMID:20684608]

9. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

10. Löhn M, Plettenburg O, Ivashchenko Y, Kannt A, Hofmeister A, Kadereit D, Schaefer M, Linz W, Kohlmann M, Herbert JM et al.. (2009) Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension, 54 (3): 676-83. [PMID:19597037]

11. Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM et al.. (2012) Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm, 3 (6): 699-709. [PMID:23275831]

12. Ray P, Wright J, Adam J, Bennett J, Boucharens S, Black D, Cook A, Brown AR, Epemolu O, Fletcher D et al.. (2011) Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors. Bioorg. Med. Chem. Lett., 21 (1): 97-101. [PMID:21145740]

13. Sturdivant JM, Royalty SM, Lin CW, Moore LA, Yingling JD, Laethem CL, Sherman B, Heintzelman GR, Kopczynski CC, deLong MA. (2016) Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett., 26 (10): 2475-80. [PMID:27072905]

14. Tamura M, Nakao H, Yoshizaki H, Shiratsuchi M, Shigyo H, Yamada H, Ozawa T, Totsuka J, Hidaka H. (2005) Development of specific Rho-kinase inhibitors and their clinical application. Biochim. Biophys. Acta, 1754 (1-2): 245-52. [PMID:16213195]

15. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M et al.. (1997) Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature, 389 (6654): 990-4. [PMID:9353125]

16. Williams RD, Novack GD, van Haarlem T, Kopczynski C, AR-12286 Phase 2A Study Group. (2011) Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol., 152 (5): 834-41.e1. [PMID:21794845]

17. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

18. Wu F, Büttner FH, Chen R, Hickey E, Jakes S, Kaplita P, Kashem MA, Kerr S, Kugler S, Paw Z et al.. (2010) Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account. Bioorg. Med. Chem. Lett., 20 (11): 3235-9. [PMID:20462760]

19. Zanin-Zhorov A, Flynn R, Waksal SD, Blazar BR. (2016) Isoform-specific targeting of ROCK proteins in immune cells. Small GTPases, 7 (3): 173-7. [PMID:27254302]

How to cite this page

Rho kinase: Rho associated coiled-coil containing protein kinase 2. Last modified on 05/04/2018. Accessed on 20/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1504.