Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTW20TU)

• DTT Name: TRAIL receptor 2 (TRAIL-R2)
• Synonyms: ZTNFR9; UNQ160/PRO186; Tumor necrosis factor receptor superfamily member 10B; TRICK2; TRAILR2; TNF-related apoptosis-inducing ligand receptor 2; KILLER; Death receptor 5; DR5; CD262
• Gene Name: TNFRSF10B
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Cytokine receptor
• UniProt ID: TR10B_HUMAN
• TTD ID: T70067
• Sequence:
  MEQRGQNAPAASGARKRHGPGPREARGARPGPRVPKTLVLVVAAVLLLVSAESALITQQD
  LAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLRCTRCD
  SGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSDIECVH
  KESGTKHSGEVPAVEETVTSSPGTPASPCSLSGIIIGVTVAAVVLIVAVFVCKSLLWKKV
  LPYLKGICSGGGGDPERVDRSSQRPGAEDNVLNEIVSILQPTQVPEQEMEVQEPAEPTGV
  NMLSPGESEHLLEPAEAERSQRRRLLVPANEGDPTETLRQCFDDFADLVPFDSWEPLMRK
  LGLMDNEIKVAKAEAAGHRDTLYTMLIKWVNKTGRDASVHTLLDALETLGERLAKQKIED
  HLLSSGKFMYLEGNADSAMS
• Function: The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B. Essential for ER stress-induced apoptosis. Receptor for the cytotoxic ligand TNFSF10/TRAIL.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  p53 signaling pathway (hsa04115)
  Apoptosis (hsa04210)
  Natural killer cell mediated cytotoxicity (hsa04650)
  Measles (hsa05162)
  Influenza A (hsa05164)
• Reactome Pathway:
  Regulation by c-FLIP (R-HSA-3371378)
  RIPK1-mediated regulated necrosis (R-HSA-5213460)
  CASP8 activity is inhibited (R-HSA-5218900)
  Dimerization of procaspase-8 (R-HSA-69416)
  TRAIL signaling (R-HSA-75158)
  Ligand-dependent caspase activation (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DTT

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Conatumumab	DM2UOSN	Colorectal cancer	2B91.Z	Phase 2	[1]
Lexatumumab	DMOS5JZ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]
Anti-DR5 cells	DMYKZB3	Hepatocellular carcinoma	2C12.02	Phase 1/2	[3]
BI 905711	DME9NYV	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
DS-8273	DMJPUDW	Colorectal cancer	2B91.Z	Phase 1	[5]
GEN1029	DMV8IWJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
IGM-8444	DMFJXDZ	Hematologic tumour	2B33.Y	Phase 1	[7]
INBRX-109	DMUNSPI	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RhApo2L/TRAIL	DMIAZJ9	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1/2	[1]
HGS-TR2J	DM0W2TA	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[9]
LBY-135	DMSRD5U	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[10]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AD5-10	DMV48L3	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]
DR-5/DR-4 cross reactive mabs	DMX2TZD	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	1.03E-05	1.09	4.71

References

• [1] Clinical pipeline report, company report or official report of Amgen (2009).
• [2] National Cancer Institute Drug Dictionary (drug id 528015).
• [3] ClinicalTrials.gov (NCT03638206) Autologous CAR-T/TCR-T Cell Immunotherapy for Malignancies
• [4] Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist. Mol Cancer Ther. 2021 Jan;20(1):96-108.
• [5] First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors. Invest New Drugs. 2017 Jun;35(3):298-306.
• [6] National Cancer Institute Drug Dictionary (drug name Tilogotamab).
• [7] Clinical pipeline report, company report or official report of IGM Biosciences.
• [8] Clinical pipeline report, company report or official report of Inhibrx.
• [9] Enhancement of Glioma Radiation Therapy and Chemotherapy Response with Targeted Antibody Therapy Against Death Receptor 5. Int J Radiat Oncol Biol Phys. 2008 June 1; 71(2): 507-516.
• [10] Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors. Invest New Drugs. 2014 Feb;32(1):135-44.
• [11] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1880).