Details of Drug Off-Target (DOT)

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

• DOT Name: Apoptosis-inducing factor 3 (AIFM3)
• Synonyms: EC 1.-.-.-; Apoptosis-inducing factor-like protein
• Gene Name: AIFM3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colonic neoplasm
  Neoplasm
  Testicular germ cell tumor
• UniProt ID: AIFM3_HUMAN
• PDB ID: 5O9V; 6QRM; 6SJZ; 6SK3; 6SK8; 6SKJ
• EC Number: 1.-.-.-
• Pfam ID: PF07992 ; PF14759 ; PF00355
• Sequence:
  MGGCFSKPKPVELKIEVVLPEKERGKEELSASGKGSPRAYQGNGTARHFHTEERLSTPHP
  YPSPQDCVEAAVCHVKDLENGQMREVELGWGKVLLVKDNGEFHALGHKCPHYGAPLVKGV
  LSRGRVRCPWHGACFNISTGDLEDFPGLDSLHKFQVKIEKEKVYVRASKQALQLQRRTKV
  MAKCISPSAGYSSSTNVLIVGAGAAGLVCAETLRQEGFSDRIVLCTLDRHLPYDRPKLSK
  SLDTQPEQLALRPKEFFRAYGIEVLTEAQVVTVDVRTKKVVFKDGFKLEYSKLLLAPGSS
  PKTLSCKGKEVENVFTIRTPEDANRVVRLARGRNVVVVGAGFLGMEVAAYLTEKAHSVSV
  VELEETPFRRFLGERVGRALMKMFENNRVKFYMQTEVSELRGQEGKLKEVVLKSSKVVRA
  DVCVVGIGAVPATGFLRQSGIGLDSRGFIPVNKMMQTNVPGVFAAGDAVTFPLAWRNNRK
  VNIPHWQMAHAQGRVAAQNMLAQEAEMSTVPYLWTAMFGKSLRYAGYGEGFDDVIIQGDL
  EELKFVAFYTKGDEVIAVASMNYDPIVSKVAEVLASGRAIRKREVELFVLHSKTGDMSWL
  TGKGS
• Function: Induces apoptosis through a caspase dependent pathway. Reduces mitochondrial membrane potential.
• Tissue Specificity: Ubiquitous. Expressed in bone marrow, cerebral cortex, liver, ovary, thymus, thyroid gland and tongue (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Apoptosis-inducing factor 3 (AIFM3) decreases the response to substance of Camptothecin.	[12]

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 Apoptosis-inducing factor 3 (AIFM3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Apoptosis-inducing factor 3 (AIFM3).	[9]

7 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 Apoptosis-inducing factor 3 (AIFM3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apoptosis-inducing factor 3 (AIFM3).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Apoptosis-inducing factor 3 (AIFM3).	[7]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Apoptosis-inducing factor 3 (AIFM3).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Apoptosis-inducing factor 3 (AIFM3).	[10]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Apoptosis-inducing factor 3 (AIFM3).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Apoptosis-inducing factor 3 (AIFM3).	[11]

References

• [1] Clinical implications of a novel prognostic factor AIFM3 in breast cancer patients.BMC Cancer. 2019 May 14;19(1):451. doi: 10.1186/s12885-019-5659-4.
• [2] AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells.EMBO J. 2005 Aug 3;24(15):2815-26. doi: 10.1038/sj.emboj.7600746. Epub 2005 Jul 7.
• [3] Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] 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.
• [12] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.