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Rho associated coiled-coil containing protein kinase 2

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Immunopharmacology Ligand 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

Gene and Protein Information Click here for help
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 Click here for help
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 Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
HSD1590 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.9 pKd 10
pKd 7.9 (Kd 1.125x10-8 M) [10]
cortistatin A Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pKd 7
pKd 6.7 (Kd 2.2x10-7 M) [7]
netarsudil Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 8.7 pKi 18
pKi 8.7 (Ki 2x10-9 M) [18]
SAR407899 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pKi 15
pKi 7.4 (Ki 3.6x10-8 M) [15]
SAR407899 Small molecule or natural product Rn Inhibition 7.4 pKi 15
pKi 7.4 (Ki 4.1x10-8 M) [15]
Y27632 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 – 6.9 pKi 15,20
pKi 6.8 – 6.9 (Ki 1.4x10-7 – 1.14x10-7 M) [15,20]
fasudil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 pKi 15
pKi 6.6 (Ki 2.71x10-7 M) [15]
HSD1590 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.3 pIC50 10
pIC50 9.3 (IC50 5.1x10-10 M) [10]
RKI-1447 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >9.0 pIC50 16
pIC50 >9.0 (IC50 <1x10-9 M) [16]
compound 11d [DOI: 10.1039/c0md00194e] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition >9.0 pIC50 8
pIC50 >9.0 (IC50 <1x10-9 M) [8]
compound 35 [PMID: 20684608] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition >9.0 pIC50 12
pIC50 >9.0 (IC50 <1x10-9 M) [12]
compound 8 [PMID: 25898023] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition >9.0 pIC50 3
pIC50 >9.0 (IC50 <1x10-9 M) [3]
Description: Measured in a commercial radiometric kinase inhibition assay.
GSK269962A Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.4 pIC50 11
pIC50 8.4 (IC50 4x10-9 M) [11]
Description: In vitro inhibitory activity against recombinant ROCK2.
compound 32 [PMID: 20471253] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.4 pIC50 5
pIC50 8.4 (IC50 4x10-9 M) [5]
compound 18 [PMID: 24119557] Small molecule or natural product Hs Inhibition 8.3 pIC50 4
pIC50 8.3 (IC50 5.1x10-9 M) [4]
ROCK inhibitor 3 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.1 pIC50 6
pIC50 8.1 (IC50 7.8x10-9 M) [6]
netarsudil Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 7.9 pIC50 10
pIC50 7.9 (IC50 1.12x10-8 M) [10]
Rho kinase inhibitor IV Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.9 pIC50 19
pIC50 7.9 (IC50 1.18x10-8 M) [19]
compound 22 [PMID: 20462760] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.7 pIC50 23
pIC50 7.7 (IC50 1.9x10-8 M) [23]
ripasudil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.7 pIC50 14
pIC50 7.7 (IC50 1.9x10-8 M) [14]
SAR407899 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pIC50 15
pIC50 7.0 (IC50 1.02x10-7 M) [15]
belumosudil Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pIC50 2
pIC50 7.0 (IC50 1.05x10-7 M) [2]
Description: In a radiometric cell-free enzyme assay.
Y27632 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 – 7.2 pIC50 15,23
pIC50 6.3 – 7.2 (IC50 4.87x10-7 – 6.1x10-8 M) [15,23]
fasudil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.9 – 5.9 pIC50 15,17
pIC50 5.9 – 5.9 (IC50 1.349x10-6 – 1.29x10-6 M) [15,17]
verosudil Small molecule or natural product Click here for species-specific activity table Hs Inhibition - - 21
[21]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen Click here for help
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: 9,22

Key to terms and symbols Click column headers to sort
Target used in screen: ROCK2
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.6 pKd
ruxolitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.2 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
tofacitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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 Click here for help
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: 1,13

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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.7 1.0 0.0
Rho kinase inhibitor IV Small molecule or natural product Hs Inhibitor Inhibition 3.2 1.0 -1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 0.0 1.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 11.7 5.0 1.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.4 8.0 0.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 17.3 10.0 1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 18.5 15.0 2.0
JNJ-7706621 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 18.6 16.0 3.0
Y27632 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 26.3 19.0 4.0
alsterpaullone 2-cyanoethyl Small molecule or natural product 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 [24]. 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. Boland S, Bourin A, Alen J, Geraets J, Schroeders P, Castermans K, Kindt N, Boumans N, Panitti L, Fransen S et al.. (2015) Design, synthesis, and biological evaluation of novel, highly active soft ROCK inhibitors. J. Med. Chem., 58 (10): 4309-24. [PMID:25898023]

4. Boland S, Defert O, Alen J, Bourin A, Castermans K, Kindt N, Boumans N, Panitti L, Van de Velde S, Stalmans I et al.. (2013) 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett., 23 (23): 6442-6. [PMID:24119557]

5. 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]

6. Cantoni S, Cavalli S, Pastore F, Accetta A, Pala D, Vaccaro F, Cesari N, De Logu F, Nassini R, Villetti G et al.. (2019) Pharmacological characterization of a highly selective Rho kinase (ROCK) inhibitor and its therapeutic effects in experimental pulmonary hypertension. Eur. J. Pharmacol., 850: 126-134. [PMID:30753868]

7. 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]

8. 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. Medchemcomm, 2: 73-75.

9. 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]

10. Dayal N, Mikek CG, Hernandez D, Naclerio GA, Yin Chu EF, Carter-Cooper BA, Lapidus RG, Sintim HO. (2019) Potently inhibiting cancer cell migration with novel 3H-pyrazolo[4,3-f]quinoline boronic acid ROCK inhibitors. Eur J Med Chem, 180: 449-456. DOI: 10.1016/j.ejmech.2019.06.089 [PMID:31330446]

11. 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]

12. 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]

13. 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]

14. Isobe T, Mizuno K, Kaneko Y, Ohta M, Koide T, Tanabe S. (2014) Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr. Eye Res., 39 (8): 813-22. [PMID:24502505]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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]

24. 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 25/02/2020. Accessed on 24/10/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1504.