Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV83SGI)

• DOT Name: Inactive tyrosine-protein kinase PRAG1 (PRAG1)
• Synonyms: PEAK1-related kinase-activating pseudokinase 1; Pragmin; Sugen kinase 223; SgK223
• Gene Name: PRAG1
• Related Disease:
  Advanced cancer
  Matthew-Wood syndrome
• UniProt ID: PRAG1_HUMAN
• PDB ID: 5VE6; 8DGN
• Pfam ID: PF07714
• Sequence:
  MHQTLCLNPESLKMSACSDFVEHIWKPGSCKNCFCLRSDHQLVAGPPQPRAGSLPPPPRL
  PPRPENCRLEDEGVNSSPYSKPTIAVKPTMMSSEASDVWTEANLSAEVSQVIWRRAPGKL
  PLPKQEDAPVVYLGSFRGVQKPAGPSTSPDGNSRCPPAYTMVGLHNLEPRGERNIAFHPV
  SFPEEKAVHKEKPSFPYQDRPSTQESFRQKLAAFAGTTSGCHQGPGPLRESLPSEDDSDQ
  RCSPSGDSEGGEYCSILDCCPGSPVAKAASQTAGSRGRHGGRDCSPTCWEQGKCSGPAEQ
  EKRGPSFPKECCSQGPTAHPSCLGPKKLSLTSEAAISSDGLSCGSGSGSGSGASSPFVPH
  LESDYCSLMKEPAPEKQQDPGCPGVTPSRCLGLTGEPQPPAHPREATQPEPIYAESTKRK
  KAAPVPSKSQAKIEHAAAAQGQGQVCTGNAWAQKAASGWGRDSPDPTPQVSATITVMAAH
  PEEDHRTIYLSSPDSAVGVQWPRGPVSQNSEVGEEETSAGQGLSSRESHAHSASESKPKE
  RPAIPPKLSKSSPVGSPVSPSAGGPPVSPLADLSDGSSGGSSIGPQPPSQGPADPAPSCR
  TNGVAISDPSRCPQPAASSASEQRRPRFQAGTWSRQCRIEEEEEVEQELLSHSWGRETKN
  GPTDHSNSTTWHRLHPTDGSSGQNSKVGTGMSKSASFAFEFPKDRSGIETFSPPPPPPKS
  RHLLKMNKSSSDLEKVSQGSAESLSPSFRGVHVSFTTGSTDSLASDSRTCSDGGPSSELA
  HSPTNSGKKLFAPVPFPSGSTEDVSPSGPQQPPPLPQKKIVSRAASSPDGFFWTQGSPKP
  GTASPKLNLSHSETNVHDESHFSYSLSPGNRHHPVFSSSDPLEKAFKGSGHWLPAAGLAG
  NRGGCGSPGLQCKGAPSASSSQLSVSSQASTGSTQLQLHGLLSNISSKEGTYAKLGGLYT
  QSLARLVAKCEDLFMGGQKKELHFNENNWSLFKLTCNKPCCDSGDAIYYCATCSEDPGST
  YAVKICKAPEPKTVSYCSPSVPVHFNIQQDCGHFVASVPSSMLSSPDAPKDPVPALPTHP
  PAQEQDCVVVITREVPHQTASDFVRDSAASHQAEPEAYERRVCFLLLQLCNGLEHLKEHG
  IIHRDLCLENLLLVHCTLQAGPGPAPAPAPAPAPAAAAPPCSSAAPPAGGTLSPAAGPAS
  PEGPREKQLPRLIISNFLKAKQKPGGTPNLQQKKSQARLAPEIVSASQYRKFDEFQTGIL
  IYELLHQPNPFEVRAQLRERDYRQEDLPPLPALSLYSPGLQQLAHLLLEADPIKRIRIGE
  AKRVLQCLLWGPRRELVQQPGTSEEALCGTLHNWIDMKRALMMMKFAEKAVDRRRGVELE
  DWLCCQYLASAEPGALLQSLKLLQLL
• Function: Catalytically inactive protein kinase that acts as a scaffold protein. Functions as an effector of the small GTPase RND2, which stimulates RhoA activity and inhibits NGF-induced neurite outgrowth. Promotes Src family kinase (SFK) signaling by regulating the subcellular localization of CSK, a negative regulator of these kinases, leading to the regulation of cell morphology and motility by a CSK-dependent mechanism. Acts as a critical coactivator of Notch signaling.
• Reactome Pathway: RND2 GTPase cycle (R-HSA-9696270)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[21]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Inactive tyrosine-protein kinase PRAG1 (PRAG1).	[22]

References

• [1] The pseudokinases SgK269 and SgK223: A novel oncogenic alliance in human cancer.Cell Adh Migr. 2018;12(6):524-528. doi: 10.1080/19336918.2017.1394570. Epub 2017 Dec 21.
• [2] The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1/Stat3 signaling.Mol Cancer. 2015 Jul 29;14:139. doi: 10.1186/s12943-015-0412-3.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [22] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.