Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5YU2XB)

• DOT Name: Tumor necrosis factor receptor superfamily member 5 (CD40)
• Synonyms: B-cell surface antigen CD40; Bp50; CD40L receptor; CDw40; CD antigen CD40
• Gene Name: CD40
• Related Disease: Hyper-IgM syndrome type 3
• UniProt ID: TNR5_HUMAN
• PDB ID: 1CZZ; 1D00; 1FLL; 1LB6; 3QD6; 5DMI; 5DMJ; 5IHL; 6FAX; 6PE8; 6PE9; 7P3I
• Pfam ID: PF00020
• Sequence:
  MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECL
  PCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCV
  LHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTN
  KTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPD
  DLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
• Function: Receptor for TNFSF5/CD40LG. Transduces TRAF6- and MAP3K8-mediated signals that activate ERK in macrophages and B cells, leading to induction of immunoglobulin secretion.
• Tissue Specificity: B-cells and in primary carcinomas.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
  Cell adhesion molecules (hsa04514)
  Toll-like receptor sig.ling pathway (hsa04620)
  Intesti.l immune network for IgA production (hsa04672)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Transcriptio.l misregulation in cancer (hsa05202)
  Asthma (hsa05310)
  Autoimmune thyroid disease (hsa05320)
  Systemic lupus erythematosus (hsa05322)
  Allograft rejection (hsa05330)
  Primary immunodeficiency (hsa05340)
  Viral myocarditis (hsa05416)
  Lipid and atherosclerosis (hsa05417)

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 3	DISVVXUI	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Tumor necrosis factor receptor superfamily member 5 (CD40) decreases the response to substance of Fluorouracil.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[13]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[14]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[15]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[16]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[17]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[18]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[19]
Carbachol	DMX9K8F	Approved	Carbachol increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[20]
Betamethasone valerate	DMMIAXO	Approved	Betamethasone valerate decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[8]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[22]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[23]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[16]
MLN4924	DMP36KD	Phase 3	MLN4924 affects the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[24]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[27]
Tesmilifene	DMPB36I	Discontinued in Phase 2	Tesmilifene decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[30]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[31]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[32]
muramyl dipeptide	DM4FR71	Investigative	muramyl dipeptide increases the expression of Tumor necrosis factor receptor superfamily member 5 (CD40).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Tumor necrosis factor receptor superfamily member 5 (CD40).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tumor necrosis factor receptor superfamily member 5 (CD40).	[26]

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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [6] 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.
• [7] 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000 Mar 1;164(5):2405-11. doi: 10.4049/jimmunol.164.5.2405.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Treatment of chronic lymphocytic leukemia with a hypomethylating agent induces expression of NXF2, an immunogenic cancer testis antigen. Clin Cancer Res. 2009 May 15;15(10):3406-15. doi: 10.1158/1078-0432.CCR-08-2099. Epub 2009 Apr 28.
• [10] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [14] Chemicals with weak skin sensitizing properties can be identified using low-density microarrays on immature dendritic cells. Toxicol Lett. 2007 Nov 1;174(1-3):98-109. doi: 10.1016/j.toxlet.2007.08.015. Epub 2007 Sep 5.
• [15] 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.
• [16] 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.
• [17] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [18] Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NF-kappaB signaling axis. Leukemia. 2010 Aug;24(8):1476-86. doi: 10.1038/leu.2010.117. Epub 2010 Jun 3.
• [19] Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol. 2015 Apr;35(4):398-406. doi: 10.1002/jat.3033. Epub 2014 Aug 4.
• [20] Muscarinic cholinoceptor activation modulates DNA synthesis and CD40 expression in fibroblast cells. Auton Autacoid Pharmacol. 2006 Jul;26(3):293-301. doi: 10.1111/j.1474-8673.2006.00369.x.
• [21] Pimecrolimus leads to an apoptosis-induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2005 Jun;115(6):1276-83. doi: 10.1016/j.jaci.2005.02.011.
• [22] Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res. 2005 Sep-Oct;25(5):3293-302.
• [23] Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res. 2009 May;77(3):314-26.
• [24] The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-B activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin Cancer Res. 2014 Mar 15;20(6):1576-89. doi: 10.1158/1078-0432.CCR-13-0987.
• [25] NF-kappaB plays a major role in the maturation of human dendritic cells induced by NiSO(4) but not by DNCB. Toxicol Sci. 2007 Oct;99(2):488-501. doi: 10.1093/toxsci/kfm178. Epub 2007 Jul 16.
• [26] 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.
• [27] Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers. EMBO Mol Med. 2013 Aug;5(8):1180-95. doi: 10.1002/emmm.201202034. Epub 2013 Jul 4.
• [28] Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation. Immunol Lett. 2001 Apr 2;76(3):175-82. doi: 10.1016/s0165-2478(01)00184-5.
• [29] Genome-wide expression changes induced by bisphenol A, F and S in human stem cell derived hepatocyte-like cells. EXCLI J. 2020 Nov 4;19:1459-1476. doi: 10.17179/excli2020-2934. eCollection 2020.
• [30] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [31] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
• [32] 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.
• [33] Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun. 2005 Dec;73(12):7967-76. doi: 10.1128/IAI.73.12.7967-7976.2005.
• [34] CD40 signaling activated by agonistic anti-CD40 monoclonal antibody 5C11 has different effects on biological behavior of gastric carcinoma cells. Immunol Lett. 2010 Jul 8;131(2):120-5. doi: 10.1016/j.imlet.2010.02.007. Epub 2010 Feb 25.