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Rho associated coiled-coil containing protein kinase 2

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Target id: 1504

Nomenclature: Rho associated coiled-coil containing protein kinase 2

Abbreviated Name: Rho kinase 2

Systematic Nomenclature: ROCK2

Family: Rho kinase

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1388 2p25.1 ROCK2 Rho associated coiled-coil containing protein kinase 2
Mouse - 1388 12 A1.1 Rock2 Rho-associated coiled-coil containing protein kinase 2
Rat - 1388 6q16 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
Alphafold O75116 (Hs), P70336 (Mm), Q62868 (Rn)
BRENDA 2.7.11.1
CATH/Gene3D 2.30.29.30
ChEMBL Target CHEMBL2973 (Hs), CHEMBL5490 (Rn)
Ensembl Gene ENSG00000134318 (Hs), ENSMUSG00000020580 (Mm), ENSRNOG00000004496 (Rn)
Entrez Gene 9475 (Hs), 19878 (Mm), 25537 (Rn)
Human Protein Atlas ENSG00000134318 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:9475 (Hs), mmu:19878 (Mm), rno:25537 (Rn)
OMIM 604002 (Hs)
Pharos O75116 (Hs)
RefSeq Nucleotide NM_004850 (Hs), NM_009072 (Mm), NM_013022 (Rn)
RefSeq Protein NP_004841 (Hs), NP_033098 (Mm), NP_037154 (Rn)
UniProtKB O75116 (Hs), P70336 (Mm), Q62868 (Rn)
Wikipedia ROCK2 (Hs)
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 20
⤷ pKi 8.7 (Ki 2x10-9 M) [20]
SAR407899 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pKi 17
⤷ pKi 7.4 (Ki 3.6x10-8 M) [17]
SAR407899 Small molecule or natural product Rn Inhibition 7.4 pKi 17
⤷ pKi 7.4 (Ki 4.1x10-8 M) [17]
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 17,22
⤷ pKi 6.8 – 6.9 (Ki 1.4x10-7 – 1.14x10-7 M) [17,22]
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 17
⤷ pKi 6.6 (Ki 2.71x10-7 M) [17]
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 18
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [18]
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.
compound 23 [PMID: 35816678] Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.5 pIC50 16
⤷ pIC50 >8.5 (IC50 <3x10-9 M) [16]
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]
sovesudil 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 Ligand has a PDB structure Hs Inhibition 7.9 pIC50 21
⤷ pIC50 7.9 (IC50 1.18x10-8 M) [21]
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 25
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [25]
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 17
⤷ pIC50 7.0 (IC50 1.02x10-7 M) [17]
belumosudil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure 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 17,25
⤷ pIC50 6.3 – 7.2 (IC50 4.87x10-7 – 6.1x10-8 M) [17,25]
zelasudil Small molecule or natural product Hs Inhibition >6.5 pIC50 15
⤷ pIC50 >6.5 (IC50 <3x10-7 M) [15]
Description: Binned IC50 value from patent ; setermined in an ADP-Glo Kinase Assay (Promega)
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 17,19
⤷ pIC50 5.9 – 5.9 (IC50 1.349x10-6 – 1.29x10-6 M) [17,19]
verosudil Small molecule or natural product Click here for species-specific activity table Hs Inhibition - - 23
⤷ [23]
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: 9,24
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 Ligand has a PDB structure 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 Ligand has a PDB structure 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 [26]. 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

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. Jones CD, Bunyard P, Pitt G, Byrne L, Pesnot T, Guisot NES. (2021) Heterocyclylamino-substituted triazoles as modulators of rho-associated protein kinase. Patent number: EP3743420B1. Assignee: Redx Pharma PLC. Priority date: 25/01/2019. Publication date: 15/12/2021.

16. Ladduwahetty T, Lee MR, Maillard MC, Cachope R, Todd D, Barnes M, Beaumont V, Chauhan A, Gallati C, Haughan AF et al.. (2022) Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington's Disease. J Med Chem, 65 (14): 9819-9845. [PMID:35816678]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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]

26. 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 21/02/2023. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1504.