Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZN7RP)

• DTT Name: Rho-associated protein kinase 1 (ROCK1)
• Synonyms: Rok; Rho-associated, coiled-coil containing protein kinase 1; Rho-associated kinase 1; Rho kinase; ROCK1; ROCK; P160ROCK; P160(rock); P160 ROCK-1; Let-502 kinase
• Gene Name: ROCK1
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: ROCK1_HUMAN
• TTD ID: T51282
• Sequence:
  MSTGDSFETRFEKMDNLLRDPKSEVNSDCLLDGLDALVYDLDFPALRKNKNIDNFLSRYK
  DTINKIRDLRMKAEDYEVVKVIGRGAFGEVQLVRHKSTRKVYAMKLLSKFEMIKRSDSAF
  FWEERDIMAFANSPWVVQLFYAFQDDRYLYMVMEYMPGGDLVNLMSNYDVPEKWARFYTA
  EVVLALDAIHSMGFIHRDVKPDNMLLDKSGHLKLADFGTCMKMNKEGMVRCDTAVGTPDY
  ISPEVLKSQGGDGYYGRECDWWSVGVFLYEMLVGDTPFYADSLVGTYSKIMNHKNSLTFP
  DDNDISKEAKNLICAFLTDREVRLGRNGVEEIKRHLFFKNDQWAWETLRDTVAPVVPDLS
  SDIDTSNFDDLEEDKGEEETFPIPKAFVGNQLPFVGFTYYSNRRYLSSANPNDNRTSSNA
  DKSLQESLQKTIYKLEEQLHNEMQLKDEMEQKCRTSNIKLDKIMKELDEEGNQRRNLEST
  VSQIEKEKMLLQHRINEYQRKAEQENEKRRNVENEVSTLKDQLEDLKKVSQNSQLANEKL
  SQLQKQLEEANDLLRTESDTAVRLRKSHTEMSKSISQLESLNRELQERNRILENSKSQTD
  KDYYQLQAILEAERRDRGHDSEMIGDLQARITSLQEEVKHLKHNLEKVEGERKEAQDMLN
  HSEKEKNNLEIDLNYKLKSLQQRLEQEVNEHKVTKARLTDKHQSIEEAKSVAMCEMEKKL
  KEEREAREKAENRVVQIEKQCSMLDVDLKQSQQKLEHLTGNKERMEDEVKNLTLQLEQES
  NKRLLLQNELKTQAFEADNLKGLEKQMKQEINTLLEAKRLLEFELAQLTKQYRGNEGQMR
  ELQDQLEAEQYFSTLYKTQVKELKEEIEEKNRENLKKIQELQNEKETLATQLDLAETKAE
  SEQLARGLLEEQYFELTQESKKAASRNRQEITDKDHTVSRLEEANSMLTKDIEILRRENE
  ELTEKMKKAEEEYKLEKEEEISNLKAAFEKNINTERTLKTQAVNKLAEIMNRKDFKIDRK
  KANTQDLRKKEKENRKLQLELNQEREKFNQMVVKHQKELNDMQAQLVEECAHRNELQMQL
  ASKESDIEQLRAKLLDLSDSTSVASFPSADETDGNLPESRIEGWLSVPNRGNIKRYGWKK
  QYVVVSSKKILFYNDEQDKEQSNPSMVLDIDKLFHVRPVTQGDVYRAETEEIPKIFQILY
  ANEGECRKDVEMEPVQQAEKTNFQNHKGHEFIPTLYHFPANCDACAKPLWHVFKPPPALE
  CRRCHVKCHRDHLDKKEDLICPCKVSYDVTSARDMLLLACSQDEQKKWVTHLVKKIPKNP
  PSGFVRASPRTLSTRSTANQSFRKVVKNTSGKTS
• 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.
• KEGG Pathway:
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  Sphingolipid signaling pathway (hsa04071)
  Vascular smooth muscle contraction (hsa04270)
  TGF-beta signaling pathway (hsa04350)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Oxytocin signaling pathway (hsa04921)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  G alpha (12/13) signalling events (R-HSA-416482)
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate ROCKs (R-HSA-5627117)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Netarsudil	DM0LPI9	Open-angle glaucoma	9C61	Approved	[1]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
H-1152	DM8XH3S	Pulmonary arterial hypertension	BB01.0	Phase 2	[2]
SAR-407899	DMF95KD	Diabetic nephropathy	GB61.Z	Phase 2	[3]
INS-117548	DMA46DO	Glaucoma/ocular hypertension	9C61	Phase 1	[4]
GSK269962A	DM5I2HL	Inflammation	1A00-CA43.1	Clinical trial	[5]

9 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID28048944-Compound-19	DMPT3V9	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-2	DM9ZXOP	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-20	DM19BQ6	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-21	DMPNG9C	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-3	DM1BN74	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-4	DMJAUWG	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-5	DMAB987	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-6	DM5RCBV	N. A.	N. A.	Patented	[6]
PMID28048944-Compound-7	DMXZ368	N. A.	N. A.	Patented	[6]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CDE-5110	DMGQ9WP	Inflammation	1A00-CA43.1	Terminated	[7]

20 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(4-Fluoro-phenyl)-(9H-purin-6-yl)-amine	DM75EAT	Discovery agent	N.A.	Investigative	[8]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[9]
Acid-activated omeprazole	DMTOEJX	Discovery agent	N.A.	Investigative	[10]
AMA-237	DMW9TRD	Chronic obstructive pulmonary disease	CA22	Investigative	[11]
AS-1892802	DMS86PI	Pain	MG30-MG3Z	Investigative	[11]
ATS-907	DMHEK4U	Glaucoma/ocular hypertension	9C61	Investigative	[11]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[12]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[12]
Fasudil	DMTCNOM	Discovery agent	N.A.	Investigative	[13]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[12]
KT-5720	DM9J50F	Discovery agent	N.A.	Investigative	[12]
PMID19364658C33	DMSE1C3	Discovery agent	N.A.	Investigative	[14]
PMID20462760C22	DMQFKBI	Discovery agent	N.A.	Investigative	[15]
PMID20684608C35	DMVUEZI	Discovery agent	N.A.	Investigative	[16]
RKI-1447	DMGTAWC	Discovery agent	N.A.	Investigative	[17]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[12]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[12]
SB-747651A	DM20Q5O	Discovery agent	N.A.	Investigative	[18]
SR-3850	DM3Y09Z	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]
TRN-101	DMXNSTF	Chronic obstructive pulmonary disease	CA22	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	2.28E-01	-0.07	-0.58
Asthma	CA23	Nasal and bronchial airway	9.78E-05	-0.25	-0.6
Chronic obstructive pulmonary disease	CA23	Lung tissue	3.93E-01	0.09	0.25
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	3.48E-01	0.07	0.23

References

• [1] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [2] Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.
• [3] The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. J Hypertens. 2012 May;30(5):980-9.
• [4] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [5] Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007 Jan;320(1):89-98.
• [6] Rho kinase inhibitors: a patent review (2014 - 2016).Expert Opin Ther Pat. 2017 Apr;27(4):507-515.
• [7] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025959)
• [8] Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22.
• [9] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [10] Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res. 2004 Jan 9;94(1):46-52.
• [11] URL: 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).
• [12] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [13] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [14] Identification 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.
• [15] Substituted 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.
• [16] Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J Med Chem. 2010 Aug 12;53(15):5727-37.
• [17] Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun 1;3(6):699-709.
• [18] 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-o... J Med Chem. 2008 Sep 25;51(18):5663-79.