Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT402Y)

• DTT Name: Stimulator of interferon genes protein (TMEM173)
• Synonyms: Mediator of IRF3 activation; Endoplasmic reticulum interferon stimulator; ERIS
• Gene Name: TMEM173
• DTT Type: Clinical trial target; [1]
• BioChemical Class: TMEM173 family
• UniProt ID: STING_HUMAN
• TTD ID: T99338
• Sequence:
  MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLL
  NGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWM
  LALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIR
  TYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVY
  SNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILA
  DAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQE
  PELLISGMEKPLPLRTDFS
• Function: Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway. Essential for the induction of IFN-beta in response to human herpes simplex virus 1 (HHV-1) infection. Exhibits 2',3' phosphodiester linkage-specific ligand recognition. Can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263).
• KEGG Pathway:
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  Cytosolic DNA-sensing pathway (hsa04623)
  Human cytomegalovirus infection (hsa05163)
  Herpes simplex virus 1 infection (hsa05168)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)
  STAT6-mediated induction of chemokines (R-HSA-3249367)
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  Neutrophil degranulation (R-HSA-6798695)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  STING mediated induction of host immune responses (R-HSA-1834941)

Molecular Interaction Atlas (MIA) of This DTT

15 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ADU- S100	DMM6B2Y	Head and neck cancer	2D42	Phase 2	[2]
ADU-S100	DM8HBUI	Head and neck cancer	2D42	Phase 2	[1]
MK-1454	DMEDITW	Squamous head and neck cell carcinom	2D60.0	Phase 2	[3]
IMSA101	DM43ICH	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[4]
A296	DMY4DUY	Aggressive cancer	2A00-2F9Z	Phase 1	[5]
BMS-986301	DMM3DBU	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
E7766	DM8TU5R	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
GSK3745417	DMRYNJD	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
MK-2118	DMKNH8B	Lymphoma	2A80-2A86	Phase 1	[9]
SB 11285	DMZ9YWG	Head-neck squamous cell carcinoma	2D60.0	Phase 1	[10]
SNX281	DMCGPU8	Lymphoma	2A80-2A86	Phase 1	[11]
SYNB1891	DMZJNHM	Lymphoma	2A80-2A86	Phase 1	[12]
TAK-500	DMVZ2FG	Aggressive cancer	2A00-2F9Z	Phase 1	[13]
TAK-676	DMCKF5J	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
XMT-2056	DM904CF	Aggressive cancer	2A00-2F9Z	Phase 1	[15]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
C-176	DMKGSRZ	Aicardi-Goutieres syndrome	5C55.2	Investigative	[16]
C-178	DM4FEU8	Aicardi-Goutieres syndrome	5C55.2	Investigative	[17]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Magnitude of Therapeutic STING Activation Determines CD8 + T Cell-Mediated Anti-tumor Immunity. Cell Rep. 2018 Dec 11;25(11):3074-3085.e5.
• [3] National Cancer Institute Drug Dictionary (drug name MK1454).
• [4] Clinical pipeline report, company report or official report of ImmuneSensor Therapeutics.
• [5] Clinical pipeline report, company report or official report of Klus Pharma
• [6] Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy. J Clin Med. 2020 Oct 16;9(10):3323.
• [7] E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity. ChemMedChem. 2021 Jun 7;16(11):1740-1743.
• [8] National Cancer Institute Drug Dictionary (drug name GSK3745417).
• [9] National Cancer Institute Drug Dictionary (drug name ML2118).
• [10] Clinical pipeline report, company report or official report of F-star Therapeutics.
• [11] Clinical pipeline report, company report or official report of Silicon Therapeutics.
• [12] Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nat Commun. 2020 Jun 1;11(1):2739.
• [13] ClinicalTrials.gov (NCT05070247) An Open-label, Dose Escalation and Expansion, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or Metastatic Solid Tumors. U.S.National Institutes of Health.
• [14] National Cancer Institute Drug Dictionary (drug name TAK676).
• [15] Clinical pipeline report, company report or official report of GlaxoSmithKline
• [16] Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage. J Neuroinflammation. 2020 May 25;17(1):165.
• [17] Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273.