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Rho associated coiled-coil containing protein kinase 1

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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

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1354 18q11.1 ROCK1 Rho associated coiled-coil containing protein kinase 1
Mouse - 1354 18 A1 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 Click here for help
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 Click here for help
Alphafold Q13464 (Hs), P70335 (Mm), Q63644 (Rn)
BRENDA 2.7.11.1
CATH/Gene3D 2.30.29.30
ChEMBL Target CHEMBL3231 (Hs), CHEMBL5509 (Rn)
Ensembl Gene ENSG00000067900 (Hs), ENSMUSG00000024290 (Mm), ENSRNOG00000031092 (Rn)
Entrez Gene 6093 (Hs), 19877 (Mm), 81762 (Rn)
Human Protein Atlas ENSG00000067900 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:6093 (Hs), mmu:19877 (Mm), rno:81762 (Rn)
OMIM 601702 (Hs)
Pharos Q13464 (Hs)
RefSeq Nucleotide NM_005406 (Hs), NM_009071 (Mm), NM_031098 (Rn)
RefSeq Protein NP_005397 (Hs), NP_033097 (Mm), NP_112360 (Rn)
SynPHARM 81347 (in complex with fasudil)
81345 (in complex with fasudil)
81554 (in complex with RKI-1447)
81707 (in complex with Y27632)
78584 (in complex with Y27632)
UniProtKB Q13464 (Hs), P70335 (Mm), Q63644 (Rn)
Wikipedia ROCK1 (Hs)
Selected 3D Structures Click here for help
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 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 8.8 pKd 8
⤷ pKd 8.8 (Kd 1.65x10-9 M) [8]
cortistatin A Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 pKd 6
⤷ pKd 6.6 (Kd 2.5x10-7 M) [6]
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 7.0 pKi 20
⤷ pKi 7.0 (Ki 1x10-7 M) [20]
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 pKi 22
⤷ pKi 6.8 (Ki 1.4x10-7 M) [22]
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 19
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [19]
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.
HSD1590 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.9 pIC50 8
⤷ pIC50 8.9 (IC50 1.22x10-9 M) [8]
GSK269962A Small molecule or natural product Primary target of this compound Click here for species-specific activity table 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] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 11
⤷ pIC50 8.0 (IC50 1x10-8 M) [11]
ROCK inhibitor 3 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.0 pIC50 5
⤷ pIC50 8.0 (IC50 1x10-8 M) [5]
GSK429286A Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 13
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [13]
netarsudil Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 7.5 pIC50 8
⤷ pIC50 7.5 (IC50 3.26x10-8 M) [8]
compound 22 [PMID: 20462760] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 25
⤷ pIC50 7.4 (IC50 3.9x10-8 M) [25]
ripasudil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.3 pIC50 14
⤷ pIC50 7.3 (IC50 5.1x10-8 M) [14]
compound 33 [PMID: 19364658] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 16
⤷ pIC50 7.2 (IC50 6x10-8 M) [16]
compound E22 [PMID: 31298542] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 10
⤷ pIC50 7.2 (IC50 6.4x10-8 M) [10]
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 5.9 – 7.3 pIC50 17,25
⤷ pIC50 5.9 – 7.3 (IC50 1.29x10-6 – 4.6x10-8 M) [17,25]
SAR407899 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.6 pIC50 17
⤷ pIC50 6.6 (IC50 2.76x10-7 M) [17]
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 5.5 – 5.6 pIC50 17,20
⤷ pIC50 5.5 – 5.6 (IC50 3.16x10-6 – 2.67x10-6 M) [17,20]
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 4.6 pIC50 2
⤷ pIC50 4.6 (IC50 2.4x10-5 M) [2]
Description: In a radiometric cell-free enzyme assay.
verosudil Small molecule or natural product Click here for species-specific activity table Hs Inhibition - - 23
⤷ [23]
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: 7,24
Key to terms and symbols Click column headers to sort
Target used in screen: ROCK1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.6 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
ruxolitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.2 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
tofacitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.3 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand 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 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: 1,12
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.2 6.0 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.6 4.5 1.5
Rho kinase inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.4 34.0 14.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 26.0 59.0 23.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 31.2 50.0 12.0
Y27632 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 31.5 77.0 31.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 37.8 89.0 29.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 38.1 86.0 24.0
alsterpaullone 2-cyanoethyl Small molecule or natural product Hs Inhibitor Inhibition 38.9 52.0 24.0
JNJ-7706621 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 42.6 65.0 16.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

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, 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]

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 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1503.