Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9E8HR)

• DTT Name: Osteoclast differentiation factor (ODF)
• Synonyms: Tumor necrosis factor ligand superfamily member 11; TRANCE; TNF-related activation-induced cytokine; Receptor activatorof nuclear factor kappa B ligand; Receptor activator of nuclear factor kappa-B ligand; RANKL; Osteoprotegerin ligand; OPGL; CD254
• Gene Name: TNFSF11
• DTT Type: Successful target; [1]
• BioChemical Class: Cytokine: tumor necrosis factor
• UniProt ID: TNF11_HUMAN
• TTD ID: T21334
• Sequence:
  MRRASRDYTKYLRGSEEMGGGPGAPHEGPLHAPPPPAPHQPPAASRSMFVALLGLGLGQV
  VCSVALFFYFRAQMDPNRISEDGTHCIYRILRLHENADFQDTTLESQDTKLIPDSCRRIK
  QAFQGAVQKELQHIVGSQHIRAEKAMVDGSWLDLAKRSKLEAQPFAHLTINATDIPSGSH
  KVSLSSWYHDRGWAKISNMTFSNGKLIVNQDGFYYLYANICFRHHETSGDLATEYLQLMV
  YVTKTSIKIPSSHTLMKGGSTKYWSGNSEFHFYSINVGGFFKLRSGEEISIEVSNPSLLD
  PDQDATYFGAFKVRDID
• Function: 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. Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B signaling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Prolactin signaling pathway (hsa04917)
  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 DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Denosumab	DMNI0KO	Drug-induced osteoporosis		Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALX-0141	DMBGI74	Osteoporosis	FB83.0	Phase 1	[2]
CEP-37251	DMYXQBF	Bone metastases	2D50	Phase 1	[3]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoporosis	FA20	Bone marrow	6.42E-01	-0.16	-0.37
Rheumatoid arthritis	FA20	Synovial tissue	1.51E-02	0.53	1.49

References

• [1] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [2] Clinical pipeline report, company report or official report of Ablynx.
• [3] This week in therapeutics Cancer. SciBX 3(40); doi:10.1038/scibx.2010.1202. Oct. 14, 2010