Target Information

Target General Infomation
Target ID
T07102
Former ID
TTDC00202
Target Name
Rho-associated protein kinase 1
Gene Name
ROCK1
Synonyms
Let-502 kinase; P160 ROCK-1; P160(rock); P160ROCK; ROCK; Rho kinase; Rho-associated kinase; Rho-associated protein kinase; Rho-associated, coiled-coil containing protein kinase; Rho-associated, coiled-coil containing protein kinase 1; Rok; ROCK1
Target Type
Clinical Trial
Disease Atherosclerosis [ICD9: 414.0, 440; ICD10: I70]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Diabetic nephropathy [ICD9: 250.4; ICD10: E11.21]
Glaucoma [ICD9: 365; ICD10: H40-H42]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Pulmonary arterial hypertension [ICD9: 416; ICD10: I27.0, I27.2]
Function
Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress. Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis. Plays a role in terminal erythroid differentiation. May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles. Promotes keratinocyte terminal differentiation. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization.
BioChemical Class
Kinase
Target Validation
T07102
UniProt ID
Q13464
EC Number
EC 2.7.11.1
Sequence
MSTGDSFETRFEKMDNLLRDPKSEVNSDCLLDGLDALVYDLDFPALRKNKNIDNFLSRYK
DTINKIRDLRMKAEDYEVVKVIGRGAFGEVQLVRHKSTRKVYAMKLLSKFEMIKRSDSAF
FWEERDIMAFANSPWVVQLFYAFQDDRYLYMVMEYMPGGDLVNLMSNYDVPEKWARFYTA
EVVLALDAIHSMGFIHRDVKPDNMLLDKSGHLKLADFGTCMKMNKEGMVRCDTAVGTPDY
ISPEVLKSQGGDGYYGRECDWWSVGVFLYEMLVGDTPFYADSLVGTYSKIMNHKNSLTFP
DDNDISKEAKNLICAFLTDREVRLGRNGVEEIKRHLFFKNDQWAWETLRDTVAPVVPDLS
SDIDTSNFDDLEEDKGEEETFPIPKAFVGNQLPFVGFTYYSNRRYLSSANPNDNRTSSNA
DKSLQESLQKTIYKLEEQLHNEMQLKDEMEQKCRTSNIKLDKIMKELDEEGNQRRNLEST
VSQIEKEKMLLQHRINEYQRKAEQENEKRRNVENEVSTLKDQLEDLKKVSQNSQLANEKL
SQLQKQLEEANDLLRTESDTAVRLRKSHTEMSKSISQLESLNRELQERNRILENSKSQTD
KDYYQLQAILEAERRDRGHDSEMIGDLQARITSLQEEVKHLKHNLEKVEGERKEAQDMLN
HSEKEKNNLEIDLNYKLKSLQQRLEQEVNEHKVTKARLTDKHQSIEEAKSVAMCEMEKKL
KEEREAREKAENRVVQIEKQCSMLDVDLKQSQQKLEHLTGNKERMEDEVKNLTLQLEQES
NKRLLLQNELKTQAFEADNLKGLEKQMKQEINTLLEAKRLLEFELAQLTKQYRGNEGQMR
ELQDQLEAEQYFSTLYKTQVKELKEEIEEKNRENLKKIQELQNEKETLATQLDLAETKAE
SEQLARGLLEEQYFELTQESKKAASRNRQEITDKDHTVSRLEEANSMLTKDIEILRRENE
ELTEKMKKAEEEYKLEKEEEISNLKAAFEKNINTERTLKTQAVNKLAEIMNRKDFKIDRK
KANTQDLRKKEKENRKLQLELNQEREKFNQMVVKHQKELNDMQAQLVEECAHRNELQMQL
ASKESDIEQLRAKLLDLSDSTSVASFPSADETDGNLPESRIEGWLSVPNRGNIKRYGWKK
QYVVVSSKKILFYNDEQDKEQSNPSMVLDIDKLFHVRPVTQGDVYRAETEEIPKIFQILY
ANEGECRKDVEMEPVQQAEKTNFQNHKGHEFIPTLYHFPANCDACAKPLWHVFKPPPALE
CRRCHVKCHRDHLDKKEDLICPCKVSYDVTSARDMLLLACSQDEQKKWVTHLVKKIPKNP
PSGFVRASPRTLSTRSTANQSFRKVVKNTSGKTS
Drugs and Mode of Action
Drug(s) Fasudil Drug Info Phase 3 Discovery agent [468243], [522059]
CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
H-1152 Drug Info Phase 2 Pulmonary arterial hypertension [544408]
SAR-407899 Drug Info Phase 2 Diabetic nephropathy [522687]
INS-117548 Drug Info Phase 1 Glaucoma [522456]
GSK269962A Drug Info Clinical trial Inflammatory disease [528461]
CDE-5110 Drug Info Terminated Inflammatory disease [548487]
Inhibitor (4-Fluoro-phenyl)-(9H-purin-6-yl)-amine Drug Info [527421]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Drug Info [527308]
5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE Drug Info [551374]
AMA-237 Drug Info [543433]
AS-1892802 Drug Info [543433]
ATS-907 Drug Info [543433]
BISINDOLYLMALEIMIDE IX Drug Info [525872]
CDE-5110 Drug Info [548488]
CI-1040 Drug Info [525872]
compound 22 Drug Info [530910]
compound 33 Drug Info [530078]
compound 35 Drug Info [531084]
Fasudil Drug Info [535190]
GF-109203 Drug Info [525872]
GSK269962A Drug Info [528461]
H-1152 Drug Info [536294]
H-1152P Drug Info [535541]
Hydroxyfasudil Drug Info [535867]
KN-62 Drug Info [525872]
KT-5720 Drug Info [525872]
RKI-1447 Drug Info [532172]
RO-316233 Drug Info [525872]
ROCK-1 inhibitors Drug Info [543433]
SAR-407899 Drug Info [531827]
SB-747651A Drug Info [529701]
SR-3850 Drug Info [543433]
TRN-101 Drug Info [543433]
Modulator INS-117548 Drug Info [1572591]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway cGMP-PKG signaling pathway
cAMP signaling pathway
Chemokine signaling pathway
Sphingolipid signaling pathway
Vascular smooth muscle contraction
TGF-beta signaling pathway
Axon guidance
Focal adhesion
Platelet activation
Leukocyte transendothelial migration
Regulation of actin cytoskeleton
Oxytocin signaling pathway
Pathogenic Escherichia coli infection
Shigellosis
Salmonella infection
Pathways in cancer
Proteoglycans in cancer
MicroRNAs in cancer
PANTHER Pathway Cytoskeletal regulation by Rho GTPase
Inflammation mediated by chemokine and cytokine signaling pathway
CCKR signaling map ST
Pathway Interaction Database Signaling events mediated by PRL
RhoA signaling pathway
Noncanonical Wnt signaling pathway
EPHB forward signaling
Thromboxane A2 receptor signaling
PAR4-mediated thrombin signaling events
amb2 Integrin signaling
Integrins in angiogenesis
EPHA forward signaling
Stabilization and expansion of the E-cadherin adherens junction
Signaling events mediated by VEGFR1 and VEGFR2
PAR1-mediated thrombin signaling events
N-cadherin signaling events
Reactome Apoptotic cleavage of cellular proteins
EPHB-mediated forward signaling
EPHA-mediated growth cone collapse
G alpha (12/13) signalling events
Sema4D induced cell migration and growth-cone collapse
VEGFA-VEGFR2 Pathway
RHO GTPases Activate ROCKs
WikiPathways G13 Signaling Pathway
Regulation of Actin Cytoskeleton
EGF/EGFR Signaling Pathway
TGF beta Signaling Pathway
Focal Adhesion
JAK/STAT
AGE/RAGE pathway
Pathogenic Escherichia coli infection
Regulation of Microtubule Cytoskeleton
Leptin signaling pathway
Semaphorin interactions
Integrin-mediated Cell Adhesion
GPCR downstream signaling
Apoptotic execution phase
MicroRNAs in cardiomyocyte hypertrophy
Androgen receptor signaling pathway
References
Ref 468243(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5181).
Ref 521505ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 522059ClinicalTrials.gov (NCT00498615) A Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon. U.S. National Institutes of Health.
Ref 522456ClinicalTrials.gov (NCT00767793) A Placebo-Controlled Study of INS117548 Ophthalmic Solution in Subjects With Glaucoma (P08650). U.S. National Institutes of Health.
Ref 522687ClinicalTrials.gov (NCT00914277) SAR407899 Single-dose in Treatment of Mild to Moderate Erectile Dysfunction. U.S. National Institutes of Health.
Ref 528461Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007 Jan;320(1):89-98. Epub 2006 Oct 3.
Ref 541019(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5676).
Ref 544408An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthalmol. 2014; 8: 883-890.
Ref 548487Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025959)
Ref
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 527421J Med Chem. 2005 Feb 10;48(3):710-22.Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.
Ref 528461Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007 Jan;320(1):89-98. Epub 2006 Oct 3.
Ref 529701J Med Chem. 2008 Sep 25;51(18):5663-79.Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.
Ref 530078Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem. 2009 May 1;17(9):3342-51.
Ref 530910Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3235-9.
Ref 531084Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J Med Chem. 2010 Aug 12;53(15):5727-37.
Ref 531827The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. J Hypertens. 2012 May;30(5):980-9.
Ref 532172Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun 1;3(6):699-709. Epub 2012 Jan 27.
Ref 535190Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo. Cardiovasc Res. 2001 Jul;51(1):169-77.
Ref 535541The novel and specific Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol Ther. 2002 Feb-Mar;93(2-3):225-32.
Ref 535867Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res. 2004 Jan 9;94(1):46-52. Epub 2003 Nov 13.
Ref 536294Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.
Ref 543433(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1503).
Ref 548488Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025959)
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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