Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSG6XGF)

• DOT Name: Forkhead box protein P1 (FOXP1)
• Synonyms: Mac-1-regulated forkhead; MFH
• Gene Name: FOXP1
• Related Disease:
  Intellectual disability-severe speech delay-mild dysmorphism syndrome
  Congenital heart disease
• UniProt ID: FOXP1_HUMAN
• PDB ID: 2KIU
• Pfam ID: PF00250 ; PF16159
• Sequence:
  MMQESGTETKSNGSAIQNGSGGSNHLLECGGLREGRSNGETPAVDIGAADLAHAQQQQQQ
  ALQVARQLLLQQQQQQQVSGLKSPKRNDKQPALQVPVSVAMMTPQVITPQQMQQILQQQV
  LSPQQLQVLLQQQQALMLQQQQLQEFYKKQQEQLQLQLLQQQHAGKQPKEQQQVATQQLA
  FQQQLLQMQQLQQQHLLSLQRQGLLTIQPGQPALPLQPLAQGMIPTELQQLWKEVTSAHT
  AEETTGNNHSSLDLTTTCVSSSAPSKTSLIMNPHASTNGQLSVHTPKRESLSHEEHPHSH
  PLYGHGVCKWPGCEAVCEDFQSFLKHLNSEHALDDRSTAQCRVQMQVVQQLELQLAKDKE
  RLQAMMTHLHVKSTEPKAAPQPLNLVSSVTLSKSASEASPQSLPHTPTTPTAPLTPVTQG
  PSVITTTSMHTVGPIRRRYSDKYNVPISSADIAQNQEFYKNAEVRPPFTYASLIRQAILE
  SPEKQLTLNEIYNWFTRMFAYFRRNAATWKNAVRHNLSLHKCFVRVENVKGAVWTVDEVE
  FQKRRPQKISGNPSLIKNMQSSHAYCTPLNAALQASMAENSIPLYTTASMGNPTLGNLAS
  AIREELNGAMEHTNSNESDSSPGRSPMQAVHPVHVKEEPLDPEEAEGPLSLVTTANHSPD
  FDHDRDYEDEPVNEDME
• Function: Transcriptional repressor. Can act with CTBP1 to synergistically repress transcription but CTPBP1 is not essential. Plays an important role in the specification and differentiation of lung epithelium. Acts cooperatively with FOXP4 to regulate lung secretory epithelial cell fate and regeneration by restricting the goblet cell lineage program; the function may involve regulation of AGR2. Essential transcriptional regulator of B-cell development. Involved in regulation of cardiac muscle cell proliferation. Involved in the columnar organization of spinal motor neurons. Promotes the formation of the lateral motor neuron column (LMC) and the preganglionic motor column (PGC) and is required for respective appropriate motor axon projections. The segment-appropriate generation of spinal cord motor columns requires cooperation with other Hox proteins. Can regulate PITX3 promoter activity; may promote midbrain identity in embryonic stem cell-derived dopamine neurons by regulating PITX3. Negatively regulates the differentiation of T follicular helper cells T(FH)s. Involved in maintenance of hair follicle stem cell quiescence; the function probably involves regulation of FGF18. Represses transcription of various pro-apoptotic genes and cooperates with NF-kappa B-signaling in promoting B-cell expansion by inhibition of caspase-dependent apoptosis. Binds to CSF1R promoter elements and is involved in regulation of monocyte differentiation and macrophage functions; repression of CSF1R in monocytes seems to involve NCOR2 as corepressor. Involved in endothelial cell proliferation, tube formation and migration indicative for a role in angiogenesis; the role in neovascularization seems to implicate suppression of SEMA5B. Can negatively regulate androgen receptor signaling. Acts as a transcriptional activator of the FBXL7 promoter; this activity is regulated by AURKA ; [Isoform 8]: Involved in transcriptional regulation in embryonic stem cells (ESCs). Stimulates expression of transcription factors that are required for pluripotency and decreases expression of differentiation-associated genes. Has distinct DNA-binding specifities as compared to the canonical form and preferentially binds DNA with the sequence 5'-CGATACAA-3' (or closely related sequences). Promotes ESC self-renewal and pluripotency.
• Tissue Specificity: Isoform 8 is specifically expressed in embryonic stem cells.
• KEGG Pathway: MicroR.s in cancer (hsa05206)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability-severe speech delay-mild dysmorphism syndrome	DISHFIJP	Definitive	Autosomal dominant	[1]
Congenital heart disease	DISQBA23	Disputed	Autosomal dominant	[1]

21 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 Forkhead box protein P1 (FOXP1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Forkhead box protein P1 (FOXP1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Forkhead box protein P1 (FOXP1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Forkhead box protein P1 (FOXP1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein P1 (FOXP1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Forkhead box protein P1 (FOXP1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Forkhead box protein P1 (FOXP1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Forkhead box protein P1 (FOXP1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Forkhead box protein P1 (FOXP1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Forkhead box protein P1 (FOXP1).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Forkhead box protein P1 (FOXP1).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Forkhead box protein P1 (FOXP1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Forkhead box protein P1 (FOXP1).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Forkhead box protein P1 (FOXP1).	[16]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Forkhead box protein P1 (FOXP1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Forkhead box protein P1 (FOXP1).	[19]
Wortmannin	DM8EVK5	Terminated	Wortmannin decreases the expression of Forkhead box protein P1 (FOXP1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Forkhead box protein P1 (FOXP1).	[15]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Forkhead box protein P1 (FOXP1).	[23]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Forkhead box protein P1 (FOXP1).	[21]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Forkhead box protein P1 (FOXP1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Forkhead box protein P1 (FOXP1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Forkhead box protein P1 (FOXP1).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Forkhead box protein P1 (FOXP1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Forkhead box protein P1 (FOXP1).	[22]

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] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [17] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [18] 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.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] FOXP1 regulation via the PI3K/Akt/p70S6K signaling pathway in breast cancer cells. Oncol Lett. 2015 Mar;9(3):1482-1488. doi: 10.3892/ol.2015.2885. Epub 2015 Jan 16.
• [22] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [23] FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells. Chem Biol Interact. 2019 Nov 1;313:108818. doi: 10.1016/j.cbi.2019.108818. Epub 2019 Sep 5.
• [24] Circular RNA circNIPBL promotes NNK-induced DNA damage in bronchial epithelial cells via the base excision repair pathway. Arch Toxicol. 2022 Jul;96(7):2049-2065. doi: 10.1007/s00204-022-03297-z. Epub 2022 Apr 18.