Druggability & Clinical Context
Druggability
Low
Score: 0.40
Target Class
Signaling Protein
Druggability Analysis
Structural Tractability0.95
Key Metrics
PDB Structures:
59
Known Drugs:
2
Approved:
0
In Clinical Trials:
0
Drug Pipeline (2 compounds)
Therapeutic Areas:Neurodegenerative diseases (ALS, Alzheimer's disease) Neuroinflammation modulation Cancer immunotherapy Chronic inflammation Innate immune disorders
Druggability Rationale: STING1 exhibits medium druggability (0.55) supported by extensive structural data (59 PDB structures, 1.36 Å resolution) and active clinical development (DMXAA in Phase 2), demonstrating that small molecules can effectively modulate the cGAS-STING pathway. However, the signaling protein class and need for pathway selectivity (agonist vs. antagonist context-dependency) present challenges in achieving optimal therapeutic windows without off-target immune effects.
Mechanism: Small molecule agonists or antagonists of cGAS-STING pathway activation
Drug Pipeline (2 compounds)
Known Drugs:DMXAA (Clinical trials) — Cancer
C-176 (Preclinical) — Inflammation
Structural Data:PDB (59) ✓AlphaFold ✓Cryo-EM ✓
Binding Pocket Analysis:STING1 contains a dinucleotide-binding pocket within its ligand-binding domain that accommodates both endogenous cyclic dinucleotides (cGAMP) and synthetic small molecules; the pocket features multiple conformational states (open/closed) captured across the 59 PDB structures, enabling allosteric modulation. Cryo-EM and AlphaFold data support characterization of both the canonical ligand-binding site and potential allosteric pockets for selective antagonism.
Selectivity & Safety Considerations
STING1 selectivity is critical given its central role in innate immunity; off-target activation of related innate sensors (cGAS, TBK1, IRF3) could amplify undesired systemic interferon responses. The single STING1 isoform reduces isoform selectivity burden, but tissue-specific delivery and pathway context (agonism in cancer vs. antagonism in neurodegeneration) are key selectivity considerations.
Clinical Trials (3)
Relevant trials from ClinicalTrials.gov
PHASE1
NCT00856336
n=15
Refractory Tumors
Interventions: DMXAA
Sponsor: Antisoma Research | Started: 2003-05
PHASE1
NCT00832494
n=105
Non-Small Cell Lung Cancer
Interventions: DMXAA in combination with carboplatin an
Sponsor: Antisoma Research | Started: 2004-09
PHASE1
NCT01031212
Tumors
Interventions: ASA404, Cetuximab, Carboplatin
Sponsor: University of California, San Francisco | Started: 2010-01