Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDVYW2F)

• DOT Name: Pleckstrin homology domain-containing family G member 1 (PLEKHG1)
• Gene Name: PLEKHG1
• Related Disease:
  Cardiovascular disease
  High blood pressure
  Nicotine dependence
  Coronary heart disease
• UniProt ID: PKHG1_HUMAN
• Pfam ID: PF00169 ; PF00621
• Sequence:
  MELSDSDRPVSFGSTSSSASSRDSHGSFGSRMTLVSNSHMGLFNQDKEVGAIKLELIPAR
  PFSSSELQRDNPATGQQNADEGSERPPRAQWRVDSNGAPKTIADSATSPKLLYVDRVVQE
  ILETERTYVQDLKSIVEDYLDCIRDQTKLPLGTEERSALFGNIQDIYHFNSELLQDLENC
  ENDPVAIAECFVSKSEEFHIYTQYCTNYPRSVAVLTECMRNKILAKFFRERQETLKHSLP
  LGSYLLKPVQRILKYHLLLHEIENHLDKDTEGYDVVLDAIDTMQRVAWHINDMKRKHEHA
  VRLQEIQSLLTNWKGPDLTSYGELVLEGTFRIQRAKNERTLFLFDKLLLITKKRDDTFTY
  KAHILCGNLMLVEVIPKEPLSFSVFHYKNPKLQHTVQAKSQQDKRLWVLHLKRLILENHA
  AKIPAKAKQAILEMDAIHHPGFCYSPEGGTKALFGSKEGSAPYRLRRKSEPSSRSHKVLK
  TSETAQDIQKVSREEGSPQLSSARPSPAQRNSQPSSSTMISVLRAGGALRNIWTDHQIRQ
  ALFPSRRSPQENEDDEDDYQMFVPSFSSSDLNSTRLCEDSTSSRPCSWHMGQMESTETSS
  SGHRIVRRASSAGESNTCPPEIGTSDRTRELQNSPKTEGQEEMTPFGSSIELTIDDIDHV
  YDNISYEDLKLMVAKREEAESTPSKSARDSVRPKSTPELAFTKRQAGHSKGSLYAQTDGT
  LSGGEASSQSTHELQAVEENIYDTIGLPDPPSLGFKCSSLKRAKRSTFLGLEADFVCCDS
  LRPFVSQDSLQLSEDEAPYHQATPDHGYLSLLYDSPSGNLSMPHKPVSDKLSEEVDEIWN
  DLENYIKKNEDKARDRLLAAFPVSKDDVPDRLHAESTPELSRDVGRSVSTLSLPESQALL
  TPVKSRAGRASRANCPFEEDLISKEGSFMSLNRLSLASEMPLMDNPYDLANSGLSQTDPE
  NPDLGMEATDKTKSRVFMMARQYSQKIKKANQLLKVKSLELEQPPASQHQKSMHKDLAAI
  LEEKKQGGPAIGARIAEYSQLYDQIVFRESPLKIQKDGWASPQESSLLRSVSPSQVHHGS
  GDWLLHSTYSNGELADFCLPPEQDLRSRYPTFEINTKSTPRQLSAACSVPSLQTSDPLPG
  SVQRCSVVVSQPNKENWCQDHLYNSLGRKGISAKSQPYHRSQSSSSVLINKSMDSINYPS
  DVGKQQLLSLHRSSRCESHQDLLPDIADSHQQGTEKLSDLTLQDSQKVVVVNRNLPLNAQ
  IATQNYFSNFKETDGDEDDYVEIKSEEDESELELSHNRRRKSDSKFVDADFSDNVCSGNT
  LHSLNSPRTPKKPVNSKLGLSPYLTPYNDSDKLNDYLWRGPSPNQQNIVQSLREKFQCLS
  SSSFA
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[2]
Nicotine dependence	DISZD9W7	Strong	Biomarker	[3]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Nicotine	DMWX5CO	Approved	Pleckstrin homology domain-containing family G member 1 (PLEKHG1) affects the response to substance of Nicotine.	[3]

2 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 Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Pleckstrin homology domain-containing family G member 1 (PLEKHG1).	[16]

References

• [1] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [2] Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.PLoS Genet. 2017 May 12;13(5):e1006728. doi: 10.1371/journal.pgen.1006728. eCollection 2017 May.
• [3] Substance dependence low-density whole genome association study in two distinct American populations. Hum Genet. 2008 Jun;123(5):495-506. doi: 10.1007/s00439-008-0501-0. Epub 2008 Apr 26.
• [4] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [5] 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.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [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] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Substance dependence low-density whole genome association study in two distinct American populations. Hum Genet. 2008 Jun;123(5):495-506. doi: 10.1007/s00439-008-0501-0. Epub 2008 Apr 26.