Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYQR611)

• DOT Name: Cytotoxic T-lymphocyte protein 4 (CTLA4)
• Synonyms: Cytotoxic T-lymphocyte-associated antigen 4; CTLA-4; CD antigen CD152
• Gene Name: CTLA4
• Related Disease: Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency
• UniProt ID: CTLA4_HUMAN
• PDB ID: 1AH1; 1H6E; 1I85; 1I8L; 2X44; 3BX7; 3OSK; 5GGV; 5TRU; 5XJ3; 6RP8; 6RPJ; 6RQM; 6XY2; 7CIO; 7DV4; 7ELX; 7SU0; 7SU1; 8HIT
• Pfam ID: PF07686
• Sequence:
  MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEY
  ASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLR
  AMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFL
  LTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN
• Function: Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.
• Tissue Specificity: Widely expressed with highest levels in lymphoid tissues. Detected in activated T-cells where expression levels are 30- to 50-fold less than CD28, the stimulatory coreceptor, on the cell surface following activation.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  T cell receptor sig.ling pathway (hsa04660)
  Autoimmune thyroid disease (hsa05320)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) (R-HSA-8877330)
  CTLA4 inhibitory signaling (R-HSA-389513)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency	DISDAF1Y	Definitive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Cytotoxic T-lymphocyte protein 4 (CTLA4) increases the Periodontal disease ADR of Ciclosporin.	[9]

1 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 Cytotoxic T-lymphocyte protein 4 (CTLA4).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Cytotoxic T-lymphocyte protein 4 (CTLA4).	[3]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Cytotoxic T-lymphocyte protein 4 (CTLA4).	[4]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Cytotoxic T-lymphocyte protein 4 (CTLA4).	[5]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Cytotoxic T-lymphocyte protein 4 (CTLA4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cytotoxic T-lymphocyte protein 4 (CTLA4).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytotoxic T-lymphocyte protein 4 (CTLA4).	[8]

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] 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] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [4] 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.
• [5] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [6] 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.
• [7] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [8] 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.
• [9] Possible association of CTLA-4 gene polymorphism with cyclosporine-induced gingival overgrowth in kidney transplant recipients. Transplant Proc. 2007 Nov;39(9):2763-5. doi: 10.1016/j.transproceed.2007.09.002.