Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ZM13C)

• DOT Name: Inverted formin-2 (INF2)
• Synonyms: HBEBP2-binding protein C
• Gene Name: INF2
• Related Disease:
  Charcot-Marie-Tooth disease dominant intermediate E
  Advanced cancer
  Alport syndrome
  Chronic renal failure
  End-stage renal disease
  Focal segmental glomerulosclerosis
  Focal segmental glomerulosclerosis 5
  Kidney failure
  Lung adenocarcinoma
  Neoplasm
  Nephrotic syndrome, type 2
  Peripheral neuropathy
  Prostate cancer
  Prostate carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Triple negative breast cancer
  Familial idiopathic steroid-resistant nephrotic syndrome
  Fabry disease
  Senior-Loken syndrome
  Chronic kidney disease
  Familial nephrotic syndrome
  Intellectual disability
  Macular corneal dystrophy
  Nephrotic syndrome
  Venous thromboembolism
• UniProt ID: INF2_HUMAN
• Pfam ID: PF06367 ; PF06371 ; PF02181 ; PF02205
• Sequence:
  MSVKEGAQRKWAALKEKLGPQDSDPTEANLESADPELCIRLLQMPSVVNYSGLRKRLEGS
  DGGWMVQFLEQSGLDLLLEALARLSGRGVARISDALLQLTCVSCVRAVMNSRQGIEYILS
  NQGYVRQLSQALDTSNVMVKKQVFELLAALCIYSPEGHVLTLDALDHYKTVCSQQYRFSI
  VMNELSGSDNVPYVVTLLSVINAVILGPEDLRARTQLRNEFIGLQLLDVLARLRDLEDAD
  LLIQLEAFEEAKAEDEEELLRVSGGVDMSSHQEVFASLFHKVSCSPVSAQLLSVLQGLLH
  LEPTLRSSQLLWEALESLVNRAVLLASDAQECTLEEVVERLLSVKGRPRPSPLVKAHKSV
  QANLDQSQRGSSPQNTTTPKPSVEGQQPAAAAACEPVDHAQSESILKVSQPRALEQQAST
  PPPPPPPPLLPGSSAEPPPPPPPPPLPSVGAKALPTAPPPPPLPGLGAMAPPAPPLPPPL
  PGSCEFLPPPPPPLPGLGCPPPPPPLLPGMGWGPPPPPPPLLPCTCSPPVAGGMEEVIVA
  QVDHGLGSAWVPSHRRVNPPTLRMKKLNWQKLPSNVAREHNSMWASLSSPDAEAVEPDFS
  SIERLFSFPAAKPKEPTMVAPRARKEPKEITFLDAKKSLNLNIFLKQFKCSNEEVAAMIR
  AGDTTKFDVEVLKQLLKLLPEKHEIENLRAFTEERAKLASADHFYLLLLAIPCYQLRIEC
  MLLCEGAAAVLDMVRPKAQLVLAACESLLTSRQLPIFCQLILRIGNFLNYGSHTGDADGF
  KISTLLKLTETKSQQNRVTLLHHVLEEAEKSHPDLLQLPRDLEQPSQAAGINLEIIRSEA
  SSNLKKLLETERKVSASVAEVQEQYTERLQASISAFRALDELFEAIEQKQRELADYLCED
  AQQLSLEDTFSTMKAFRDLFLRALKENKDRKEQAAKAERRKQQLAEEEARRPRGEDGKPV
  RKGPGKQEEVCVIDALLADIRKGFQLRKTARGRGDTDGGSKAASMDPPRATEPVATSNPA
  GDPVGSTRCPASEPGLDATTASESRGWDLVDAVTPGPQPTLEQLEEGGPRPLERRSSWYV
  DASDVLTTEDPQCPQPLEGAWPVTLGDAQALKPLKFSSNQPPAAGSSRQDAKDPTSLLGV
  LQAEADSTSEGLEDAVHSRGARPPAAGPGGDEDEDEEDTAPESALDTSLDKSFSEDAVTD
  SSGSGTLPRARGRASKGTGKRRKKRPSRSQEEVPPDSDDNKTKKLCVIQ
• Function: Severs actin filaments and accelerates their polymerization and depolymerization.
• Tissue Specificity: Widely expressed. In the kidney, expression is apparent in podocytes and some tubule cells.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease dominant intermediate E	DISC8LSK	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alport syndrome	DIS25AB4	Strong	Genetic Variation	[3]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[4]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[4]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[5]
Focal segmental glomerulosclerosis 5	DIS3S9HO	Strong	Autosomal dominant	[6]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nephrotic syndrome, type 2	DISIRFO1	Strong	GermlineCausalMutation	[6]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[10]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[10]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[2]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[2]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[2]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[11]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[6]
Fabry disease	DISUUQJF	Disputed	Biomarker	[12]
Senior-Loken syndrome	DISGBSGP	Disputed	Biomarker	[12]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[4]
Familial nephrotic syndrome	DISADF8G	Limited	Genetic Variation	[13]
Intellectual disability	DISMBNXP	Limited	Biomarker	[14]
Macular corneal dystrophy	DISOLD0H	Limited	Biomarker	[4]
Nephrotic syndrome	DISSPSC2	Limited	Genetic Variation	[15]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[16]

12 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 Inverted formin-2 (INF2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inverted formin-2 (INF2).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inverted formin-2 (INF2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inverted formin-2 (INF2).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Inverted formin-2 (INF2).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Inverted formin-2 (INF2).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Inverted formin-2 (INF2).	[23]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Inverted formin-2 (INF2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Inverted formin-2 (INF2).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inverted formin-2 (INF2).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inverted formin-2 (INF2).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inverted formin-2 (INF2).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inverted formin-2 (INF2).	[21]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Inverted formin-2 (INF2).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Inverted formin-2 (INF2).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Inverted formin-2 (INF2).	[29]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission.J Cell Physiol. 2019 Sep;234(9):16238-16251. doi: 10.1002/jcp.28287. Epub 2019 Feb 11.
• [3] Familial focal segmental glomerulosclerosis: mutation in inverted formin 2 mimicking Alport syndrome.Neth J Med. 2016 Feb;74(2):82-5.
• [4] Mutational screening of inverted formin 2 in adult-onset focal segmental glomerulosclerosis or minimal change patients from the Czech Republic.BMC Med Genet. 2018 Aug 20;19(1):147. doi: 10.1186/s12881-018-0667-9.
• [5] A complex containing lysine-acetylated actin inhibits the formin INF2.Nat Cell Biol. 2019 May;21(5):592-602. doi: 10.1038/s41556-019-0307-4. Epub 2019 Apr 8.
• [6] Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet. 2010 Jan;42(1):72-6. doi: 10.1038/ng.505. Epub 2009 Dec 20.
• [7] Diagnosing FSGS without kidney biopsy - a novel INF2-mutation in a family with ESRD of unknown origin.BMC Med Genet. 2016 Oct 12;17(1):73. doi: 10.1186/s12881-016-0336-9.
• [8] Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma.Mol Carcinog. 2009 Dec;48(12):1116-22. doi: 10.1002/mc.20563.
• [9] Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy.J Neuropathol Exp Neurol. 2014 Mar;73(3):223-33. doi: 10.1097/NEN.0000000000000047.
• [10] Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer.PLoS Genet. 2017 Apr 27;13(4):e1006748. doi: 10.1371/journal.pgen.1006748. eCollection 2017 Apr.
• [11] Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities.Breast Cancer (Auckl). 2018 Aug 24;12:1178223418792247. doi: 10.1177/1178223418792247. eCollection 2018.
• [12] Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy.Clin Transplant. 2014 Sep;28(9):995-1003. doi: 10.1111/ctr.12408. Epub 2014 Jul 18.
• [13] Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis.Kidney Int. 2013 Feb;83(2):316-22. doi: 10.1038/ki.2012.349. Epub 2012 Sep 26.
• [14] De novo INF2 mutations expand the genetic spectrum of hereditary neuropathy with glomerulopathy.Neurology. 2013 Nov 26;81(22):1953-8. doi: 10.1212/01.wnl.0000436615.58705.c9. Epub 2013 Oct 30.
• [15] Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ -1) and profilin 2.Biosci Rep. 2016 Jan 13;36(1):e00302. doi: 10.1042/BSR20150252.
• [16] Discordance between surgical care improvement project adherence and postoperative outcomes: implications for new Joint Commission standards.J Surg Res. 2017 May 15;212:205-213. doi: 10.1016/j.jss.2017.01.006. Epub 2017 Jan 30.
• [17] 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.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [22] 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.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] 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.
• [25] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [26] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.