Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA9Z9OC)

• DOT Name: Forkhead box protein P3 (FOXP3)
• Synonyms: Scurfin
• Gene Name: FOXP3
• Related Disease: Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
• UniProt ID: FOXP3_HUMAN
• PDB ID: 3QRF; 4WK8
• Pfam ID: PF00250 ; PF16159
• Sequence:
  MPNPRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGGAHASSSS
  LNPMPPSQLQLPTLPLVMVAPSGARLGPLPHLQALLQDRPHFMHQLSTVDAHARTPVLQV
  HPLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSREPALLCTFPNPSAPRKD
  STLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQADHLLDEKGRAQCLLQREMVQ
  SLEQQLVLEKEKLSAMQAHLAGKMALTKASSVASSDKGSCCIVAAGSQGPVVPAWSGPRE
  APDSLFAVRRHLWGSHGNSTFPEFLHNMDYFKFHNMRPPFTYATLIRWAILEAPEKQRTL
  NEIYHWFTRMFAFFRNHPATWKNAIRHNLSLHKCFVRVESEKGAVWTVDELEFRKKRSQR
  PSRCSNPTPGP
• Function: Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg). Plays an essential role in maintaining homeostasis of the immune system by allowing the acquisition of full suppressive function and stability of the Treg lineage, and by directly modulating the expansion and function of conventional T-cells. Can act either as a transcriptional repressor or a transcriptional activator depending on its interactions with other transcription factors, histone acetylases and deacetylases. The suppressive activity of Treg involves the coordinate activation of many genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of genes encoding cytokines such as interleukin-2 (IL2) and interferon-gamma (IFNG). Inhibits cytokine production and T-cell effector function by repressing the activity of two key transcription factors, RELA and NFATC2. Mediates transcriptional repression of IL2 via its association with histone acetylase KAT5 and histone deacetylase HDAC7. Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG via its association with transcription factor RUNX1. Inhibits the differentiation of IL17 producing helper T-cells (Th17) by antagonizing RORC function, leading to down-regulation of IL17 expression, favoring Treg development. Inhibits the transcriptional activator activity of RORA. Can repress the expression of IL2 and IFNG via its association with transcription factor IKZF4.
• KEGG Pathway:
  Th17 cell differentiation (hsa04659)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  RUNX1 regulates transcription of genes involved in WNT signaling (R-HSA-8939256)
  RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) (R-HSA-8877330)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome	DIST4IL8	Definitive	X-linked	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Forkhead box protein P3 (FOXP3).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Forkhead box protein P3 (FOXP3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Forkhead box protein P3 (FOXP3).	[9]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the methylation of Forkhead box protein P3 (FOXP3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Forkhead box protein P3 (FOXP3).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Forkhead box protein P3 (FOXP3).	[4]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Forkhead box protein P3 (FOXP3).	[6]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Forkhead box protein P3 (FOXP3).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Forkhead box protein P3 (FOXP3).	[8]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the expression of Forkhead box protein P3 (FOXP3).	[10]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Forkhead box protein P3 (FOXP3).	[12]
Mepacrine	DMU8L7C	Investigative	Mepacrine increases the expression of Forkhead box protein P3 (FOXP3).	[13]

References

• [1] Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome. J Clin Endocrinol Metab. 2003 Dec;88(12):6034-9. doi: 10.1210/jc.2003-031080.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] [As(2)O(3) Up-Regulates the Proportion of CD4(+)CD25(+)CD127(low) Tregs in Peripheral Blood of Patients with Severe Aplastic Anemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018 Jun;26(3):854-858. doi: 10.7534/j.issn.1009-2137.2018.03.037.
• [4] 1,25-dihydroxyvitamin D3 (vitamin D3) catalyzes suppressive activity on human natural regulatory T cells, uniquely modulates cell cycle progression, and augments FOXP3. Clin Immunol. 2011 Feb;138(2):212-21. doi: 10.1016/j.clim.2010.11.003. Epub 2010 Dec 16.
• [5] 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.
• [6] Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance. Clin Exp Immunol. 2010 Aug;161(2):298-305. doi: 10.1111/j.1365-2249.2010.04170.x. Epub 2010 May 18.
• [7] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [8] 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.
• [9] 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.
• [10] Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. Muscle Nerve. 2017 Dec;56(6):1077-1084. doi: 10.1002/mus.25733. Epub 2017 Aug 29.
• [11] Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clin Exp Allergy. 2015 Jan;45(1):238-48. doi: 10.1111/cea.12377.
• [12] Compound C induces autophagy and apoptosis in parental and hydroquinone-selected malignant leukemia cells through the ROS/p38 MAPK/AMPK/TET2/FOXP3 axis. Cell Biol Toxicol. 2020 Aug;36(4):315-331. doi: 10.1007/s10565-019-09495-3. Epub 2020 Jan 3.
• [13] Quinacrine induces the apoptosis of human leukemia U937 cells through FOXP3/miR-183/-TrCP/SP1 axis-mediated BAX upregulation. Toxicol Appl Pharmacol. 2017 Nov 1;334:35-46. doi: 10.1016/j.taap.2017.08.019. Epub 2017 Sep 1.