Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT75Z6A6)

• DOT Name: CD40 ligand (CD40LG)
• Synonyms: CD40-L; T-cell antigen Gp39; TNF-related activation protein; TRAP; Tumor necrosis factor ligand superfamily member 5; CD antigen CD154
• Gene Name: CD40LG
• Related Disease: Hyper-IgM syndrome type 1
• UniProt ID: CD40L_HUMAN
• PDB ID: 1ALY; 1I9R; 3LKJ; 3QD6; 6BRB; 6W9G; 7SGM
• Pfam ID: PF00229
• Sequence:
  MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLH
  EDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNP
  QIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSN
  REASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVN
  VTDPSQVSHGTGFTSFGLLKL
• Function: Cytokine that acts as a ligand to CD40/TNFRSF5. Costimulates T-cell proliferation and cytokine production. Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation. Induces the activation of NF-kappa-B. Induces the activation of kinases MAPK8 and PAK2 in T-cells. Induces tyrosine phosphorylation of isoform 3 of CD28. Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4. Involved in immunoglobulin class switching; [CD40 ligand, soluble form]: Acts as a ligand for integrins, specifically ITGA5:ITGB1 and ITGAV:ITGB3; both integrins and the CD40 receptor are required for activation of CD40-CD40LG signaling, which have cell-type dependent effects, such as B-cell activation, NF-kappa-B signaling and anti-apoptotic signaling.
• Tissue Specificity: Specifically expressed on activated CD4+ T-lymphocytes.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
  Cell adhesion molecules (hsa04514)
  T cell receptor sig.ling pathway (hsa04660)
  Intesti.l immune network for IgA production (hsa04672)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Asthma (hsa05310)
  Autoimmune thyroid disease (hsa05320)
  Systemic lupus erythematosus (hsa05322)
  Allograft rejection (hsa05330)
  Primary immunodeficiency (hsa05340)
  Viral myocarditis (hsa05416)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyper-IgM syndrome type 1	DISC91LV	Definitive	X-linked	[1]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	CD40 ligand (CD40LG) decreases the response to substance of Doxorubicin.	[20]
Cisplatin	DMRHGI9	Approved	CD40 ligand (CD40LG) decreases the response to substance of Cisplatin.	[20]
Etoposide	DMNH3PG	Approved	CD40 ligand (CD40LG) decreases the response to substance of Etoposide.	[20]
Paclitaxel	DMLB81S	Approved	CD40 ligand (CD40LG) decreases the response to substance of Paclitaxel.	[20]
Vinblastine	DM5TVS3	Approved	CD40 ligand (CD40LG) decreases the response to substance of Vinblastine.	[20]

20 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 CD40 ligand (CD40LG).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of CD40 ligand (CD40LG).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of CD40 ligand (CD40LG).	[4]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of CD40 ligand (CD40LG).	[5]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of CD40 ligand (CD40LG).	[6]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of CD40 ligand (CD40LG).	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of CD40 ligand (CD40LG).	[8]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the activity of CD40 ligand (CD40LG).	[9]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of CD40 ligand (CD40LG).	[10]
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine decreases the expression of CD40 ligand (CD40LG).	[11]
Candesartan	DMRK8OT	Approved	Candesartan decreases the expression of CD40 ligand (CD40LG).	[8]
Asasantin	DMCZIHT	Approved	Asasantin decreases the expression of CD40 ligand (CD40LG).	[13]
Eptifibatide	DMQXTJS	Approved	Eptifibatide decreases the expression of CD40 ligand (CD40LG).	[10]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of CD40 ligand (CD40LG).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of CD40 ligand (CD40LG).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of CD40 ligand (CD40LG).	[17]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of CD40 ligand (CD40LG).	[18]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the expression of CD40 ligand (CD40LG).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of CD40 ligand (CD40LG).	[18]
adenosine diphosphate	DMFUHKP	Investigative	adenosine diphosphate increases the expression of CD40 ligand (CD40LG).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dipyridamole	DMXY30O	Approved	Dipyridamole decreases the secretion of CD40 ligand (CD40LG).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of CD40 ligand (CD40LG).	[16]

References

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• [2] Curcumin reduces the expression of survivin, leading to enhancement of arsenic trioxide-induced apoptosis in myelodysplastic syndrome and leukemia stem-like cells. Oncol Rep. 2016 Sep;36(3):1233-42. doi: 10.3892/or.2016.4944. Epub 2016 Jul 15.
• [3] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [4] Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol. 2009 Mar;144(5):667-76. doi: 10.1111/j.1365-2141.2008.07504.x. Epub 2008 Nov 20.
• [5] Lack of uniform platelet activation in patients after ischemic stroke and choice of antiplatelet therapy. Thromb Res. 2004;113(3-4):197-204. doi: 10.1016/j.thromres.2004.03.002.
• [6] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [7] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [8] Additive beneficial effects of fenofibrate combined with candesartan in the treatment of hypertriglyceridemic hypertensive patients. Diabetes Care. 2006 Feb;29(2):195-201. doi: 10.2337/diacare.29.02.06.dc05-1418.
• [9] Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dDelta12,14,PGJ2. Leukemia. 2009 Feb;23(2):292-304. doi: 10.1038/leu.2008.283. Epub 2008 Oct 16.
• [10] Eptifibatide in peripheral vascular interventions: results of the Integrilin Reduces Inflammation in Peripheral Vascular Interventions (INFLAME) trial. J Invasive Cardiol. 2006 Jan;18(1):6-12.
• [11] Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017 Aug 9;19(1):183. doi: 10.1186/s13075-017-1393-y.
• [12] The effect of dipyridamole on vascular cell-derived reactive oxygen species. J Pharmacol Exp Ther. 2005 Nov;315(2):494-500. doi: 10.1124/jpet.105.089987. Epub 2005 Jul 26.
• [13] Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Eur J Pharmacol. 2004 Sep 24;499(3):315-24. doi: 10.1016/j.ejphar.2004.07.114.
• [14] Effect of atorvastatin on circulating proinflammatory T-lymphocyte subsets and soluble CD40 ligand in patients with stable coronary artery disease--a randomized, placebo-controlled study. Am Heart J. 2006 Jan;151(1):139. doi: 10.1016/j.ahj.2005.10.006.
• [15] Platelet CD40 ligand (CD40L)--subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets. 2001 Mar;12(2):74-82. doi: 10.1080/09537100020031207.
• [16] 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.
• [17] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [18] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [19] 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.
• [20] CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways. BMC Cancer. 2006 Mar 18;6:75. doi: 10.1186/1471-2407-6-75.