Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVYN14T)

• DOT Name: Rho-associated protein kinase 2 (ROCK2)
• Synonyms: EC 2.7.11.1; Rho kinase 2; Rho-associated, coiled-coil-containing protein kinase 2; Rho-associated, coiled-coil-containing protein kinase II; ROCK-II; p164 ROCK-2
• Gene Name: ROCK2
• UniProt ID: ROCK2_HUMAN
• PDB ID: 4L6Q; 4WOT; 5U7Q; 5U7R; 6ED6; 6P5M; 6P5P; 7JNT; 7JOV; 7P6N; 8GDS
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF08912
• 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: 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 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.
• Tissue Specificity: Expressed in the brain (at protein level).
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Sphingolipid sig.ling pathway (hsa04071)
  Vascular smooth muscle contraction (hsa04270)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Oxytocin sig.ling pathway (hsa04921)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Lipid and atherosclerosis (hsa05417)
• 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)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOBTB1 GTPase cycle (R-HSA-9013422)
  Potential therapeutics for SARS (R-HSA-9679191)
  EPHB-mediated forward signaling (R-HSA-3928662)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Rho-associated protein kinase 2 (ROCK2) increases the response to substance of Arsenic.	[21]

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Rho-associated protein kinase 2 (ROCK2).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rho-associated protein kinase 2 (ROCK2).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho-associated protein kinase 2 (ROCK2).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho-associated protein kinase 2 (ROCK2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho-associated protein kinase 2 (ROCK2).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho-associated protein kinase 2 (ROCK2).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Rho-associated protein kinase 2 (ROCK2).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Rho-associated protein kinase 2 (ROCK2).	[6]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Rho-associated protein kinase 2 (ROCK2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Rho-associated protein kinase 2 (ROCK2).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Rho-associated protein kinase 2 (ROCK2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho-associated protein kinase 2 (ROCK2).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Rho-associated protein kinase 2 (ROCK2).	[15]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Rho-associated protein kinase 2 (ROCK2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho-associated protein kinase 2 (ROCK2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho-associated protein kinase 2 (ROCK2).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Rho-associated protein kinase 2 (ROCK2).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Rho-associated protein kinase 2 (ROCK2).	[11]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Rho-associated protein kinase 2 (ROCK2).	[11]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Rho-associated protein kinase 2 (ROCK2).	[20]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Rho-associated protein kinase 2 (ROCK2).	[11]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Rho-associated protein kinase 2 (ROCK2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rho-associated protein kinase 2 (ROCK2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rho-associated protein kinase 2 (ROCK2).	[7]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acocantherin	DM7JT24	Approved	Acocantherin increases the cleavage of Rho-associated protein kinase 2 (ROCK2).	[10]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [8] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [9] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [10] Ouabain-induced apoptosis and Rho kinase: a novel caspase-2 cleavage site and fragment of Rock-2. Apoptosis. 2010 Dec;15(12):1494-506. doi: 10.1007/s10495-010-0529-1.
• [11] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [21] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.