Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTH5DUJ)

• DOT Name: FERM domain-containing protein 8 (FRMD8)
• Synonyms: Band4.1 inhibitor LRP interactor; Bili; iRhom tail-associated protein; iTAP
• Gene Name: FRMD8
• Related Disease: Acute myelogenous leukaemia
• UniProt ID: FRMD8_HUMAN
• Pfam ID: PF00373
• Sequence:
  MDGTEGSAGQPGPAERSHRSSVSSVGARAADVLVYLADDTVVPLAVENLPSLSAHELHRA
  VREVLQLPDIALDVFALWLVSPLLEVQLKPKHQPYKLGRQWPELLLRFTSAPDDDVAMDE
  PFLQFRRNVFFPKRRELQIHDEEVLRLLYEEAKGNVLAARYPCDVEDCEALGALVCRVQL
  GPYQPGRPAACDLREKLDSFLPAHLCKRGQSLFAALRGRGARAGPGEQGLLNAYRQVQEV
  SSDGGCEAALGTHYRAYLLKCHELPFYGCAFFHGEVDKPAQGFLHRGGRKPVSVAISLEG
  VHVIDSREKHVLLGLRFQELSWDHTSPEEEEPILWLEFDGDSEGTPVNKLLKIYSKQAEL
  MSSLIEYCIELSQAAEPAGPQDSATGSPSDPSSSLAPVQRPKLRRQGSVVSSRIQHLSTI
  DYVEDGKGIRRVKPKRTTSFFSRQLSLGQGSYTVVQPGDSLEQG
• Function: Promotes the cell surface stability of iRhom1/RHBDF1 and iRhom2/RHBDF2 and prevents their degradation via the endolysosomal pathway. By acting on iRhoms, involved in ADAM17-mediated shedding of TNF, amphiregulin/AREG, HBEGF and TGFA from the cell surface. Negatively regulates Wnt signaling, possibly by antagonizing the recruitment of AXIN1 to LRP6.
• Tissue Specificity: Widely expressed, with high expression in heart and spleen.
• KEGG Pathway: TNF sig.ling pathway (hsa04668)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of FERM domain-containing protein 8 (FRMD8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of FERM domain-containing protein 8 (FRMD8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FERM domain-containing protein 8 (FRMD8).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of FERM domain-containing protein 8 (FRMD8).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of FERM domain-containing protein 8 (FRMD8).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of FERM domain-containing protein 8 (FRMD8).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of FERM domain-containing protein 8 (FRMD8).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of FERM domain-containing protein 8 (FRMD8).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of FERM domain-containing protein 8 (FRMD8).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of FERM domain-containing protein 8 (FRMD8).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of FERM domain-containing protein 8 (FRMD8).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of FERM domain-containing protein 8 (FRMD8).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of FERM domain-containing protein 8 (FRMD8).	[12]

References

• [1] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.