Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM4CHU1)

• DOT Name: Arf-GAP with dual PH domain-containing protein 1 (ADAP1)
• Synonyms: Centaurin-alpha-1; Cnt-a1; Putative MAPK-activating protein PM25
• Gene Name: ADAP1
• Related Disease:
  Alzheimer disease
  Breast neoplasm
  Neuroblastoma
• UniProt ID: ADAP1_HUMAN
• PDB ID: 3FEH; 3FM8; 3LJU; 3MDB
• Pfam ID: PF01412 ; PF00169
• Sequence:
  MAKERRRAVLELLQRPGNARCADCGAPDPDWASYTLGVFICLSCSGIHRNIPQVSKVKSV
  RLDAWEEAQVEFMASHGNDAARARFESKVPSFYYRPTPSDCQLLREQWIRAKYERQEFIY
  PEKQEPYSAGYREGFLWKRGRDNGQFLSRKFVLTEREGALKYFNRNDAKEPKAVMKIEHL
  NATFQPAKIGHPHGLQVTYLKDNSTRNIFIYHEDGKEIVDWFNALRAARFHYLQVAFPGA
  GDADLVPKLSRNYLKEGYMEKTGPKQTEGFRKRWFTMDDRRLMYFKDPLDAFARGEVFIG
  SKESGYTVLHGFPPSTQGHHWPHGITIVTPDRKFLFACETESDQREWVAAFQKAVDRPML
  PQEYAVEAHFKHKP
• Function: GTPase-activating protein for the ADP ribosylation factor family (Probable). Binds phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4).
• Tissue Specificity: Expressed at highest levels in brain and at lower levels in peripheral blood leukocytes.
• Reactome Pathway: Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[2]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arf-GAP with dual PH domain-containing protein 1 (ADAP1) decreases the response to substance of Arsenic trioxide.	[14]

3 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 Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Arf-GAP with dual PH domain-containing protein 1 (ADAP1).	[12]

References

• [1] Retinoic acid-induced upregulation of the metalloendopeptidase nardilysin is accelerated by co-expression of the brain-specific protein p42(IP4) (centaurin 1; ADAP1) in neuroblastoma cells.Neurochem Int. 2011 Nov;59(6):936-44. doi: 10.1016/j.neuint.2011.07.004. Epub 2011 Jul 23.
• [2] Genome-wide DNA methylation assessment of 'BRCA1-like' early-onset breast cancer: Data from the Australian Breast Cancer Family Registry.Exp Mol Pathol. 2018 Dec;105(3):404-410. doi: 10.1016/j.yexmp.2018.11.006. Epub 2018 Nov 10.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] 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.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] 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.
• [14] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.