Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYNVZ23)

• DOT Name: Protein FAN (NSMAF)
• Synonyms: Factor associated with neutral sphingomyelinase activation; Factor associated with N-SMase activation
• Gene Name: NSMAF
• Related Disease:
  Pulmonary tuberculosis
  Tuberculosis
  Advanced cancer
  Melanoma
  Neoplasm
• UniProt ID: FAN_HUMAN
• Pfam ID: PF02138 ; PF02893 ; PF00400
• Sequence:
  MAFIRKKQQEQQLQLYSKERFSLLLLNLEEYYFEQHRANHILHKGSHHERKIRGSLKICS
  KSVIFEPDSISQPIIKIPLRDCIKIGKHGENGANRHFTKAKSGGISLIFSQVYFIKEHNV
  VAPYKIERGKMEYVFELDVPGKVEDVVETLLQLHRASCLDKLGDQTAMITAILQSRLART
  SFDKNRFQNISEKLHMECKAEMVTPLVTNPGHVCITDTNLYFQPLNGYPKPVVQITLQDV
  RRIYKRRHGLMPLGLEVFCTEDDLCSDIYLKFYEPQDRDDLYFYIATYLEHHVAEHTAES
  YMLQWQRGHLSNYQYLLHLNNLADRSCNDLSQYPVFPWIIHDYSSSELDLSNPGTFRDLS
  KPVGALNKERLERLLTRYQEMPEPKFMYGSHYSSPGYVLFYLVRIAPEYMLCLQNGRFDN
  ADRMFNSIAETWKNCLDGATDFKELIPEFYGDDVSFLVNSLKLDLGKRQGGQMVDDVELP
  PWASSPEDFLQKSKDALESNYVSEHLHEWIDLIFGYKQKGSDAVGAHNVFHPLTYEGGVD
  LNSIQDPDEKVAMLTQILEFGQTPKQLFVTPHPRRITPKFKSLSQTSSYNASMADSPGEE
  SFEDLTEESKTLAWNNITKLQLHEHYKIHKEAVTGITVSRNGSSVFTTSQDSTLKMFSKE
  SKMLQRSISFSNMALSSCLLLPGDATVITSSWDNNVYFYSIAFGRRQDTLMGHDDAVSKI
  CWHDNRLYSASWDSTVKVWSGVPAEMPGTKRHHFDLLAELEHDVSVDTISLNAASTLLVS
  GTKEGTVNIWDLTTATLMHQIPCHSGIVCDTAFSPDSRHVLSTGTDGCLNVIDVQTGMLI
  SSMTSDEPQRCFVWDGNSVLSGSQSGELLVWDLLGAKISERIQGHTGAVTCIWMNEQCSS
  IITGGEDRQIIFWKLQY
• Function: Couples the p55 TNF-receptor (TNF-R55 / TNFR1) to neutral sphingomyelinase (N-SMASE). Specifically binds to the N-smase activation domain of TNF-R55. May regulate ceramide production by N-SMASE.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: TNFR1-mediated ceramide production (R-HSA-5626978)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary tuberculosis	DIS6FLUM	Definitive	Genetic Variation	[1]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[2]
Melanoma	DIS1RRCY	moderate	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Protein FAN (NSMAF) affects the response to substance of Topotecan.	[17]
Vinblastine	DM5TVS3	Approved	Protein FAN (NSMAF) affects the response to substance of Vinblastine.	[17]

16 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 Protein FAN (NSMAF).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein FAN (NSMAF).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein FAN (NSMAF).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein FAN (NSMAF).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein FAN (NSMAF).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein FAN (NSMAF).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Protein FAN (NSMAF).	[9]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Protein FAN (NSMAF).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Protein FAN (NSMAF).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein FAN (NSMAF).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein FAN (NSMAF).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein FAN (NSMAF).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein FAN (NSMAF).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein FAN (NSMAF).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein FAN (NSMAF).	[15]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid decreases the expression of Protein FAN (NSMAF).	[16]

References

• [1] New variant identified in major susceptibility locus to tuberculosis on chromosomal region 8q12-q13 in Moroccan population: a case control study.BMC Infect Dis. 2017 Nov 7;17(1):712. doi: 10.1186/s12879-017-2807-9.
• [2] TNF-receptor-1 adaptor protein FAN mediates TNF-induced B16 melanoma motility and invasion.Br J Cancer. 2013 Jul 23;109(2):422-32. doi: 10.1038/bjc.2013.242. Epub 2013 May 14.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [10] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [11] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.
• [15] 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.
• [16] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.