Details of Drug Off-Target (DOT)

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

• DOT Name: Tumor necrosis factor ligand superfamily member 11 (TNFSF11)
• Synonyms: Osteoclast differentiation factor; ODF; Osteoprotegerin ligand; OPGL; Receptor activator of nuclear factor kappa-B ligand; RANKL; TNF-related activation-induced cytokine; TRANCE; CD antigen CD254
• Gene Name: TNFSF11
• Related Disease:
  Autosomal recessive osteopetrosis 2
  Infantile malignant osteopetrosis
• UniProt ID: TNF11_HUMAN
• PDB ID: 3URF; 5BNQ
• Pfam ID: PF00229
• Sequence:
  MRRASRDYTKYLRGSEEMGGGPGAPHEGPLHAPPPPAPHQPPAASRSMFVALLGLGLGQV
  VCSVALFFYFRAQMDPNRISEDGTHCIYRILRLHENADFQDTTLESQDTKLIPDSCRRIK
  QAFQGAVQKELQHIVGSQHIRAEKAMVDGSWLDLAKRSKLEAQPFAHLTINATDIPSGSH
  KVSLSSWYHDRGWAKISNMTFSNGKLIVNQDGFYYLYANICFRHHETSGDLATEYLQLMV
  YVTKTSIKIPSSHTLMKGGSTKYWSGNSEFHFYSINVGGFFKLRSGEEISIEVSNPSLLD
  PDQDATYFGAFKVRDID
• Function: Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca (2+) resulting in the activation of NFATC1, which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation.
• Tissue Specificity: Highest in the peripheral lymph nodes, weak in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Prolactin sig.ling pathway (hsa04917)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Breast cancer (hsa05224)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  TNFs bind their physiological receptors (R-HSA-5669034)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive osteopetrosis 2	DISBQFGY	Strong	Autosomal recessive	[1]
Infantile malignant osteopetrosis	DIS8C3LZ	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[13]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[17]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[18]
Glucosamine	DM4ZLFD	Approved	Glucosamine increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[18]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[11]
Levonorgestrel	DM1DP7T	Approved	Levonorgestrel decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[19]
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[18]
Ozagrel	DMIGKA1	Phase 4	Ozagrel decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[24]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[25]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[6]
carbocyclic thromboxane A2	DMGKSVF	Investigative	carbocyclic thromboxane A2 increases the expression of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tumor necrosis factor ligand superfamily member 11 (TNFSF11).	[22]

References

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• [3] 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.
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• [9] Protective effects of myricitrin against osteoporosis via reducing reactive oxygen species and bone-resorbing cytokines. Toxicol Appl Pharmacol. 2014 Nov 1;280(3):550-60.
• [10] 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):381-8. doi: 10.1016/j.jsbmb.2006.12.054. Epub 2007 Feb 12.
• [11] Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor kappaB, osteoprotegerin, and receptor activator of nuclear factor kappaB ligand. Arthritis Rheum. 2004 Dec;50(12):3831-43. doi: 10.1002/art.20637.
• [12] The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res. 2004 Jan;19(1):147-54. doi: 10.1359/jbmr.2004.19.1.147.
• [13] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [14] Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and -independent mechanisms. Am J Physiol Cell Physiol. 2009 Dec;297(6):C1358-67. doi: 10.1152/ajpcell.00216.2009. Epub 2009 Aug 12.
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• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [18] Chondroitin and glucosamine sulfate in combination decrease the pro-resorptive properties of human osteoarthritis subchondral bone osteoblasts: a basic science study. Arthritis Res Ther. 2007;9(6):R117. doi: 10.1186/ar2325.
• [19] [Effect of nylestriol and levonorgestrel on the expression of Opg/OPGL in human osteosarcoma MG-63 cell lines]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004 Dec;29(6):667-70.
• [20] Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome). Nat Genet. 2008 Mar;40(3):284-6. doi: 10.1038/ng.2007.66. Epub 2008 Feb 10.
• [21] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [22] 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.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [25] Preconception exposure to dibutyl phthalate (DBP) impairs spermatogenesis by activating NF-B/COX-2/RANKL signaling in Sertoli cells. Toxicology. 2022 May 30;474:153213. doi: 10.1016/j.tox.2022.153213. Epub 2022 May 20.