Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Rho-associated protein kinase 2 (ROCK2)
• Synonyms: p164 ROCK-2; Rho-associated, coiled-coil-containing protein kinase II; Rho-associated, coiled-coil-containing protein kinase 2; Rho kinase 2; ROCK-II; KIAA0619
• Gene Name: ROCK2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: ROCK2_HUMAN
• TTD ID: T06093
• EC Number: EC 2.7.11.1
• Sequence:
  MSRPPPTGKMPGAPETAPGDGAGASRQRKLEALIRDPRSPINVESLLDGLNSLVLDLDFP
  ALRKNKNIDNFLNRYEKIVKKIRGLQMKAEDYDVVKVIGRGAFGEVQLVRHKASQKVYAM
  KLLSKFEMIKRSDSAFFWEERDIMAFANSPWVVQLFYAFQDDRYLYMVMEYMPGGDLVNL
  MSNYDVPEKWAKFYTAEVVLALDAIHSMGLIHRDVKPDNMLLDKHGHLKLADFGTCMKMD
  ETGMVHCDTAVGTPDYISPEVLKSQGGDGFYGRECDWWSVGVFLYEMLVGDTPFYADSLV
  GTYSKIMDHKNSLCFPEDAEISKHAKNLICAFLTDREVRLGRNGVEEIRQHPFFKNDQWH
  WDNIRETAAPVVPELSSDIDSSNFDDIEDDKGDVETFPIPKAFVGNQLPFIGFTYYRENL
  LLSDSPSCRETDSIQSRKNEESQEIQKKLYTLEEHLSNEMQAKEELEQKCKSVNTRLEKT
  AKELEEEITLRKSVESALRQLEREKALLQHKNAEYQRKADHEADKKRNLENDVNSLKDQL
  EDLKKRNQNSQISTEKVNQLQRQLDETNALLRTESDTAARLRKTQAESSKQIQQLESNNR
  DLQDKNCLLETAKLKLEKEFINLQSALESERRDRTHGSEIINDLQGRICGLEEDLKNGKI
  LLAKVELEKRQLQERFTDLEKEKSNMEIDMTYQLKVIQQSLEQEEAEHKATKARLADKNK
  IYESIEEAKSEAMKEMEKKLLEERTLKQKVENLLLEAEKRCSLLDCDLKQSQQKINELLK
  QKDVLNEDVRNLTLKIEQETQKRCLTQNDLKMQTQQVNTLKMSEKQLKQENNHLMEMKMN
  LEKQNAELRKERQDADGQMKELQDQLEAEQYFSTLYKTQVRELKEECEEKTKLGKELQQK
  KQELQDERDSLAAQLEITLTKADSEQLARSIAEEQYSDLEKEKIMKELEIKEMMARHKQE
  LTEKDATIASLEETNRTLTSDVANLANEKEELNNKLKDVQEQLSRLKDEEISAAAIKAQF
  EKQLLTERTLKTQAVNKLAEIMNRKEPVKRGNDTDVRRKEKENRKLHMELKSEREKLTQQ
  MIKYQKELNEMQAQIAEESQIRIELQMTLDSKDSDIEQLRSQLQALHIGLDSSSIGSGPG
  DAEADDGFPESRLEGWLSLPVRNNTKKFGWVKKYVIVSSKKILFYDSEQDKEQSNPYMVL
  DIDKLFHVRPVTQTDVYRADAKEIPRIFQILYANEGESKKEQEFPVEPVGEKSNYICHKG
  HEFIPTLYHFPTNCEACMKPLWHMFKPPPALECRRCHIKCHKDHMDKKEEIIAPCKVYYD
  ISTAKNLLLLANSTEEQQKWVSRLVKKIPKKPPAPDPFARSSPRTSMKIQQNQSIRRPSR
  QLAPNKPS
• Function: 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 ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation. Protein kinase which is a key regulator of actin cytoskeleton and cell polarity.
• KEGG Pathway:
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  Sphingolipid signaling pathway (hsa04071)
  Vascular smooth muscle contraction (hsa04270)
  Wnt signaling pathway (hsa04310)
  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)
• Reactome Pathway:
  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)
  EPHB-mediated forward signaling (R-HSA-3928662)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Belumosudil	DM548TK	Graft-versus-host disease	4B24	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
INS-117548	DMA46DO	Glaucoma/ocular hypertension	9C61	Phase 1	[2]
GSK269962A	DM5I2HL	Inflammation	1A00-CA43.1	Clinical trial	[3]

13 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Indazolyl-thiadiazolamine derivative 1	DMR2GW1	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-11	DMQ6WEN	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-19	DMPT3V9	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-2	DM9ZXOP	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-3	DM1BN74	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-4	DMJAUWG	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-5	DMAB987	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-6	DM5RCBV	N. A.	N. A.	Patented	[4]
PMID28048944-Compound-7	DMXZ368	N. A.	N. A.	Patented	[4]
Tricyclic compound 4	DMEIG16	N. A.	N. A.	Patented	[4]
Tricyclic compound 5	DMLPMS7	N. A.	N. A.	Patented	[4]
Tricyclic compound 6	DMMJ81G	N. A.	N. A.	Patented	[4]
Tricyclic compound 7	DME84S5	N. A.	N. A.	Patented	[4]

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	[5]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMA-237	DMW9TRD	Chronic obstructive pulmonary disease	CA22	Investigative	[6]
ATS-907	DMHEK4U	Glaucoma/ocular hypertension	9C61	Investigative	[6]
Glycyl-H 1152	DM0SCK8	Discovery agent	N.A.	Investigative	[7]
PMID20462760C22	DMQFKBI	Discovery agent	N.A.	Investigative	[8]
PMID20471253C32	DMBQAKO	Discovery agent	N.A.	Investigative	[9]
PMID20684608C35	DMVUEZI	Discovery agent	N.A.	Investigative	[10]
RKI-1447	DMGTAWC	Discovery agent	N.A.	Investigative	[11]
SR-3850	DM3Y09Z	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
TRN-101	DMXNSTF	Chronic obstructive pulmonary disease	CA22	Investigative	[6]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	8.76E-01	6.89E-03	0.03
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	1.39E-02	-0.09	-0.39
Rheumatoid arthritis	FA20	Synovial tissue	1.55E-01	0.12	0.71

References

• [1] Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16814-9.
• [2] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [3] Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther. 2007 Jan;320(1):89-98.
• [4] Rho kinase inhibitors: a patent review (2014 - 2016).Expert Opin Ther Pat. 2017 Apr;27(4):507-515.
• [5] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025959)
• [6] 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: 1504).
• [7] Development of specific Rho-kinase inhibitors and their clinical application. Biochim Biophys Acta. 2005 Dec 30;1754(1-2):245-52.
• [8] 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.
• [9] Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines. Bioorg Med Chem Lett. 2010 Jun 15;20(12):3746-9.
• [10] Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J Med Chem. 2010 Aug 12;53(15):5727-37.
• [11] Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun 1;3(6):699-709.