Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0MWCHG)

• DOT Name: Interleukin-2 receptor subunit alpha (IL2RA)
• Synonyms: IL-2 receptor subunit alpha; IL-2-RA; IL-2R subunit alpha; IL2-RA; TAC antigen; p55; CD antigen CD25
• Gene Name: IL2RA
• Related Disease:
  Immunodeficiency due to CD25 deficiency
  Neonatal diabetes mellitus
  Neonatal diabetes mellitus with congenital hypothyroidism
  Type 1 diabetes mellitus 10
• UniProt ID: IL2RA_HUMAN
• PDB ID: 1Z92; 2B5I; 2ERJ; 3IU3; 3NFP; 6VWU; 6YIO; 7F9W; 7ZMZ
• Pfam ID: PF00084
• Sequence:
  MDSYLLMWGLLTFIMVPGCQAELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKS
  GSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQAS
  LPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQP
  QLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQ
  VAVAGCVFLLISVLLLSGLTWQRRQRKSRRTI
• Function: Receptor for interleukin-2. The receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (TREGs) activity. TREGs suppress the activation and expansion of autoreactive T-cells.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Endocytosis (hsa04144)
  PI3K-Akt sig.ling pathway (hsa04151)
  JAK-STAT sig.ling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Measles (hsa05162)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) (R-HSA-8877330)
  Interleukin-2 signaling (R-HSA-9020558)
  Interleukin receptor SHC signaling (R-HSA-912526)
  RAF/MAP kinase cascade (R-HSA-5673001)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency due to CD25 deficiency	DISIV7MN	Strong	Autosomal recessive	[1]
Neonatal diabetes mellitus	DISFHF9K	Strong	Autosomal recessive	[2]
Neonatal diabetes mellitus with congenital hypothyroidism	DISA2P6G	Strong	Autosomal recessive	[2]
Type 1 diabetes mellitus 10	DIS9AGCD	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Interleukin-2 receptor subunit alpha (IL2RA).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Interleukin-2 receptor subunit alpha (IL2RA).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Interleukin-2 receptor subunit alpha (IL2RA).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[8]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[10]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[11]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[12]
Dinoprostone	DMTYOPD	Approved	Dinoprostone decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[13]
Zalcitabine	DMH7MUV	Approved	Zalcitabine decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[11]
Pimecrolimus	DMZLGRB	Approved	Pimecrolimus decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[4]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[15]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[16]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin affects the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[17]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[20]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[21]
PMID28870136-Compound-49	DMTUC9E	Patented	PMID28870136-Compound-49 decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[21]
D-7193	DMO9HWU	Discontinued in Phase 2	D-7193 decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[22]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[21]
Cordycepin	DM72Y01	Investigative	Cordycepin affects the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[24]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[25]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[25]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[26]
isobutylmethylxanthine	DM46F5X	Investigative	isobutylmethylxanthine decreases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[21]
ISOPENTENYL PYROPHOSPHATE	DMTU05Y	Investigative	ISOPENTENYL PYROPHOSPHATE increases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[27]
PROSTRATIN	DM1HMJ5	Investigative	PROSTRATIN increases the expression of Interleukin-2 receptor subunit alpha (IL2RA).	[28]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Clozapine increases the secretion of Interleukin-2 receptor subunit alpha (IL2RA).	[9]
Propofol	DMB4OLE	Approved	Propofol decreases the secretion of Interleukin-2 receptor subunit alpha (IL2RA).	[14]
Thiopental	DMGP8AX	Approved	Thiopental decreases the secretion of Interleukin-2 receptor subunit alpha (IL2RA).	[14]

References

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• [10] Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008 May 15;180(10):6988-96. doi: 10.4049/jimmunol.180.10.6988.
• [11] Down-regulation of interleukin-2 receptor gene activation and protein expression by dideoxynucleoside analogs. Cell Immunol. 1995 Jul;163(2):289-95. doi: 10.1006/cimm.1995.1128.
• [12] Ouabain induces inhibition of the progression phase in human T-cell proliferation. J Cell Physiol. 1995 Nov;165(2):246-53. doi: 10.1002/jcp.1041650205.
• [13] Prostaglandin E2 inhibits human T-cell proliferation after crosslinking of the CD3-Ti complex by directly affecting T cells at an early step of the activation process. Cell Immunol. 1987 Jan;104(1):24-36. doi: 10.1016/0008-8749(87)90003-7.
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• [15] Inhaled beclomethasone dipropionate downregulates airway lymphocyte activation in atopic asthma. Am J Respir Crit Care Med. 1994 Jan;149(1):86-90. doi: 10.1164/ajrccm.149.1.8111605.
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• [17] Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. J Leukoc Biol. 2006 Mar;79(3):529-38. doi: 10.1189/jlb.0205064. Epub 2005 Dec 30.
• [18] Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. J Immunol. 2002 Nov 15;169(10):5555-63. doi: 10.4049/jimmunol.169.10.5555.
• [19] 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.
• [20] 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.
• [21] Pentoxifylline and other methyl xanthines inhibit interleukin-2 receptor expression in human lymphocytes. Cell Immunol. 1991 Jul;135(2):314-25. doi: 10.1016/0008-8749(91)90276-h.
• [22] The new oral immunomodulating drug DiNAC induces brachial artery vasodilatation at rest and during hyperemia in hypercholesterolemic subjects, likely by a nitric oxide-dependent mechanism. Atherosclerosis. 2008 Jan;196(1):275-282. doi: 10.1016/j.atherosclerosis.2006.10.031. Epub 2006 Dec 8.
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• [24] Effect of cordycepin on interleukin-10 production of human peripheral blood mononuclear cells. Eur J Pharmacol. 2002 Oct 25;453(2-3):309-17. doi: 10.1016/s0014-2999(02)02359-2.
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