Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3TQM5)

• DOT Name: FUN14 domain-containing protein 2 (FUNDC2)
• Synonyms: Cervical cancer proto-oncogene 3 protein; HCC-3; Hepatitis C virus core-binding protein 6
• Gene Name: FUNDC2
• Related Disease:
  Fatty liver disease
  Haemophilia A
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Pulmonary embolism
  Stroke
  Thrombocytopenia
  Venous thromboembolism
  Melanoma
  Pancreatic cancer
• UniProt ID: FUND2_HUMAN
• Pfam ID: PF04930
• Sequence:
  METSAPRAGSQVVATTARHSAAYRADPLRVSSRDKLTEMAASSQGNFEGNFESLDLAEFA
  KKQPWWRKLFGQESGPSAEKYSVATQLFIGGVTGWCTGFIFQKVGKLAATAVGGGFFLLQ
  LANHTGYIKVDWQRVEKDMKKAKEQLKIRKSNQIPTEVRSKAEEVVSFVKKNVLVTGGFF
  GGFLLGMAS
• Function: Binds directly and specifically 1,2-Diacyl-sn-glycero-3-phospho-(1'-myo-inositol-3',4',5'-bisphosphate) (PIP3) leading to the recruitment of PIP3 to mitochondria and may play a role in the regulation of the platelet activation via AKT/GSK3B/cGMP signaling pathways. May act as transcription factor that regulates SREBP1 (isoform SREBP-1C) expression in order to modulate triglyceride (TG) homeostasis in hepatocytes.
• Tissue Specificity: Highly expressed in platelets (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Biomarker	[1]
Haemophilia A	DIS0RQ2E	Strong	Genetic Variation	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Pulmonary embolism	DISJYP9B	Strong	Genetic Variation	[4]
Stroke	DISX6UHX	Strong	Genetic Variation	[4]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[5]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[6]
Melanoma	DIS1RRCY	Limited	Biomarker	[7]
Pancreatic cancer	DISJC981	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of FUN14 domain-containing protein 2 (FUNDC2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of FUN14 domain-containing protein 2 (FUNDC2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FUN14 domain-containing protein 2 (FUNDC2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of FUN14 domain-containing protein 2 (FUNDC2).	[11]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of FUN14 domain-containing protein 2 (FUNDC2).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of FUN14 domain-containing protein 2 (FUNDC2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of FUN14 domain-containing protein 2 (FUNDC2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of FUN14 domain-containing protein 2 (FUNDC2).	[14]

References

• [1] HCBP6 Is Involved in the Development of Hepatic Steatosis Induced by High-Fat Diet and CCL4 in Rats.Ann Hepatol. 2018 May-June;17(3):511-518. doi: 10.5604/01.3001.0011.7396. Epub 2018 Apr 9.
• [2] Double complex mutations involving F8 and FUNDC2 caused by distinct break-induced replication.Hum Mutat. 2007 Dec;28(12):1198-206. doi: 10.1002/humu.20591.
• [3] MiR-223 modulates multidrug resistance via downregulation of ABCB1 in hepatocellular carcinoma cells. Exp Biol Med (Maywood). 2013 Sep;238(9):1024-32.
• [4] Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.Hum Mol Genet. 2016 May 1;25(9):1867-74. doi: 10.1093/hmg/ddw037. Epub 2016 Feb 9.
• [5] Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway.Cell Death Differ. 2019 Jan;26(2):321-331. doi: 10.1038/s41418-018-0121-8. Epub 2018 May 21.
• [6] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [7] Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model.Front Pharmacol. 2017 Jul 7;8:319. doi: 10.3389/fphar.2017.00319. eCollection 2017.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [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] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.