Rho associated coiled-coil containing protein kinase 1 | Rho kinase | IUPHAR/BPS Guide to PHARMACOLOGY

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Rho associated coiled-coil containing protein kinase 1

Target not currently curated in GtoImmuPdb

Target id: 1503

Nomenclature: Rho associated coiled-coil containing protein kinase 1

Abbreviated Name: Rho kinase 1

Systematic Nomenclature: ROCK1

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 - 1354 18q11.2 ROCK1 Rho associated coiled-coil containing protein kinase 1
Mouse - 1354 18 A2 Rock1 Rho-associated coiled-coil containing protein kinase 1
Rat - 1369 18p13 Rock1 Rho-associated coiled-coil containing protein kinase 1
Previous and Unofficial Names
p160ROCK | liver regeneration-related protein LRRG199 | p160 ROCK-1 | Rho-associated kinase beta | ROCK-I | Rho-associated, coiled-coil containing protein kinase 1
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of a coiled-coil domain from human ROCK I
PDB Id:  3O0Z
Resolution:  2.33Å
Species:  Human
References:  21
Image of receptor 3D structure from RCSB PDB
Description:  Human RHO-ASSOCIATED PROTEIN KINASE 1 (ROCK 1) IN COMPLEX WITH INDAZOLE DERIVATIVE (COMPOUND 18)
PDB Id:  3V8S
Resolution:  2.29Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  Rho-associated protein kinase 1 (ROCK 1) in complex with RKI1447.
PDB Id:  3TWJ
Ligand:  RKI-1447
Resolution:  2.9Å
Species:  Human
References:  18
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Rho-Associated Protein Kinase (ROCK1) with a potent isoquinolone derivative
PDB Id:  3NDM
Ligand:  compound 32 [PMID: 20471253]
Resolution:  3.3Å
Species:  Human
References:  4
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
HSD1590 Hs Inhibition 8.8 pKd 8
pKd 8.8 (Kd 1.65x10-9 M) [8]
cortistatin A Hs Inhibition 6.6 pKd 6
pKd 6.6 (Kd 2.5x10-7 M) [6]
fasudil Hs Inhibition 7.0 pKi 20
pKi 7.0 (Ki 1x10-7 M) [20]
Y27632 Hs Inhibition 6.8 pKi 22
pKi 6.8 (Ki 1.4x10-7 M) [22]
RKI-1447 Hs Inhibition >9.0 pIC50 19
pIC50 >9.0 (IC50 <1x10-9 M) [19]
compound 8 [PMID: 25898023] Hs Inhibition >9.0 pIC50 3
pIC50 >9.0 (IC50 <1x10-9 M) [3]
Description: Measured in a commercial radiometric kinase inhibition assay.
HSD1590 Hs Inhibition 8.9 pIC50 8
pIC50 8.9 (IC50 1.22x10-9 M) [8]
GSK269962A Hs Inhibition 8.8 pIC50 9
pIC50 8.8 (IC50 1.6x10-9 M) [9]
Description: In vitro inhibitory activity against recombinant ROCK1.
compound 35 [PMID: 20684608] Hs Inhibition 8.0 pIC50 11
pIC50 8.0 (IC50 1x10-8 M) [11]
ROCK inhibitor 3 Hs Inhibition 8.0 pIC50 5
pIC50 8.0 (IC50 1x10-8 M) [5]
GSK429286A Hs Inhibition 7.8 pIC50 13
pIC50 7.8 (IC50 1.4x10-8 M) [13]
netarsudil Hs Inhibition 7.5 pIC50 8
pIC50 7.5 (IC50 3.26x10-8 M) [8]
compound 22 [PMID: 20462760] Hs Inhibition 7.4 pIC50 25
pIC50 7.4 (IC50 3.9x10-8 M) [25]
ripasudil Hs Inhibition 7.3 pIC50 14
pIC50 7.3 (IC50 5.1x10-8 M) [14]
compound 33 [PMID: 19364658] Hs Inhibition 7.2 pIC50 16
pIC50 7.2 (IC50 6x10-8 M) [16]
compound E22 [PMID: 31298542] Hs Inhibition 7.2 pIC50 10
pIC50 7.2 (IC50 6.4x10-8 M) [10]
Y27632 Hs Inhibition 5.9 – 7.3 pIC50 17,25
pIC50 5.9 – 7.3 (IC50 1.29x10-6 – 4.6x10-8 M) [17,25]
SAR407899 Hs Inhibition 6.6 pIC50 17
pIC50 6.6 (IC50 2.76x10-7 M) [17]
fasudil Hs Inhibition 5.5 – 5.6 pIC50 17,20
pIC50 5.5 – 5.6 (IC50 3.16x10-6 – 2.67x10-6 M) [17,20]
KD025 Hs Inhibition 4.6 pIC50 2
pIC50 4.6 (IC50 2.4x10-5 M) [2]
Description: In a radiometric cell-free enzyme assay.
verosudil Hs Inhibition - - 23
[23]
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: 7,24

Key to terms and symbols Click column headers to sort
Target used in screen: ROCK1
Ligand Sp. Type Action Value Parameter
staurosporine Hs Inhibitor Inhibition 9.6 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.4 pKd
A-674563 Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Hs Inhibitor Inhibition 7.3 pKd
ruxolitinib Hs Inhibitor Inhibition 7.2 pKd
GSK690693 Hs Inhibitor Inhibition 6.6 pKd
KW-2449 Hs Inhibitor Inhibition 6.5 pKd
sunitinib Hs Inhibitor Inhibition 6.3 pKd
tofacitinib Hs Inhibitor Inhibition 6.3 pKd
tamatinib Hs Inhibitor Inhibition 6.2 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: 1,12

Key to terms and symbols Click column headers to sort
Target used in screen: ROCK-I/ROCK1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 0.2 6.0 1.0
staurosporine Hs Inhibitor Inhibition 0.6 4.5 1.5
Rho kinase inhibitor IV Hs Inhibitor Inhibition 3.4 34.0 14.0
PKR inhibitor Hs Inhibitor Inhibition 26.0 59.0 23.0
K-252a Hs Inhibitor Inhibition 31.2 50.0 12.0
Y27632 Hs Inhibitor Inhibition 31.5 77.0 31.0
H-89 Hs Inhibitor Inhibition 37.8 89.0 29.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 38.1 86.0 24.0
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 38.9 52.0 24.0
JNJ-7706621 Hs Inhibitor Inhibition 42.6 65.0 16.0
Displaying the top 10 most potent ligands  View all ligands in screen »

References

Show »

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. 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]

5. 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]

6. 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]

7. 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]

8. Dayal N, Mikek CG, Hernandez D, Naclerio GA, Chu EFY, 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. European Journal of Medicinal Chemistry, In Press, Accepted Manuscript. DOI: 10.1016/j.ejmech.2019.06.089

9. 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]

10. Dong X, Zhan W, Zhao M, Che J, Dai X, Wu Y, Xu L, Zhou Y, Zhao Y, Tian T et al.. (2019) Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design. J. Med. Chem., 62 (15): 7264-7288. [PMID:31298542]

11. 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]

12. 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]

13. Goodman KB, Cui H, Dowdell SE, Gaitanopoulos DE, Ivy RL, Sehon CA, Stavenger RA, Wang GZ, Viet AQ, Xu W et al.. (2007) Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors. J. Med. Chem., 50 (1): 6-9. [PMID:17201405]

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. Li R, Martin MP, Liu Y, Wang B, Patel RA, Zhu JY, Sun N, Pireddu R, Lawrence NJ, Li J et al.. (2012) Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J. Med. Chem., 55 (5): 2474-8. [PMID:22272748]

16. Lovering F, Kirincich S, Wang W, Combs K, Resnick L, Sabalski JE, Butera J, Liu J, Parris K, Telliez JB. (2009) Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg. Med. Chem., 17 (9): 3342-51. [PMID:19364658]

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. Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, Schönbrunn E, Lawrence NJ, Sebti SM. (2012) RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res., 72 (19): 5025-34. [PMID:22846914]

19. 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]

20. 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]

21. Tu D, Li Y, Song HK, Toms AV, Gould CJ, Ficarro SB, Marto JA, Goode BL, Eck MJ. (2011) Crystal structure of a coiled-coil domain from human ROCK I. PLoS ONE, 6 (3): e18080. [PMID:21445309]

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]

How to cite this page

Rho kinase: Rho associated coiled-coil containing protein kinase 1. Last modified on 25/09/2019. Accessed on 19/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1503.