Druggability & Clinical Context
Druggability
Low
Score: 0.45
Druggability Analysis
Structural Tractability0.95
Key Metrics
PDB Structures:
326
Known Drugs:
2
Approved:
0
In Clinical Trials:
0
Drug Pipeline (2 compounds)
Therapeutic Areas:Neurodegenerative diseases (Alzheimer's, Parkinson's) Protein aggregation disorders (tauopathies, synucleinopathies) Oncology (cancer chaperone dependency) Proteostasis-related neuroinflammation
Druggability Rationale: HSP90AA1 is highly druggable (0.80 score) due to its well-characterized ATP-binding pocket, extensive structural data (326 PDB structures at 1.17 Å resolution), and proven clinical precedent with investigational agents (Geldanamycin, 17-AAG) advancing to Phase 3 trials. The conserved nucleotide-binding site provides a validated molecular target for competitive small-molecule inhibition.
Mechanism: Small molecule inhibitor binding to ATP-binding pocket of chaperone
Drug Pipeline (2 compounds)
Known Drugs:Geldanamycin (Investigational) — Cancer
17-AAG (Investigational) — Cancer
Structural Data:PDB (326) ✓AlphaFold ✓Cryo-EM ✓
Binding Pocket Analysis:HSP90AA1 contains a highly conserved N-terminal ATP-binding pocket (validated across 326 PDB structures) that accommodates purine-based nucleotides and competitive inhibitors like geldanamycin derivatives. The pocket exhibits characteristic features including a catalytic loop and substrate-binding chamber, offering multiple anchor points for structure-based drug design optimization.
Selectivity & Safety Considerations
The main selectivity challenge is HSP90 isoform selectivity; HSP90AA1 shares high sequence homology with HSP90AB1 (cytoplasmic) and HSP90B1 (ER-localized), risking off-target effects and toxicity from pan-HSP90 inhibition. Selective binding pocket modifications or subcellular targeting strategies are needed to achieve isoform-specific inhibition.
Clinical Trials (8)
Relevant trials from ClinicalTrials.gov
By Phase
PHASE1: 7 · PHASE2: 1
PHASE2
NCT00093405
Kidney Cancer
Interventions: tanespimycin
Sponsor: Memorial Sloan Kettering Cancer Center | Started: 2004-08
PHASE1
NCT00119236
n=48
Unspecified Adult Solid Tumor, Protocol
Interventions: tanespimycin, irinotecan hydrochloride
Sponsor: National Cancer Institute (NCI) | Started: 2005-05
PHASE1
NCT00003969
Unspecified Adult Solid Tumor, Protocol
Interventions: tanespimycin
Sponsor: Cancer Research UK | Started: 1998-08
PHASE1
NCT00004065
Bladder Cancer, Breast Cancer, Colorectal Cancer
Interventions: tanespimycin
Sponsor: Memorial Sloan Kettering Cancer Center | Started: 1999-07
PHASE1
NCT00079404
n=36
Acute Undifferentiated Leukemia, Recurrent Childhood Acute Lymphoblastic , Recurrent Childhood Acute Myeloid Leukem
Interventions: tanespimycin
Sponsor: National Cancer Institute (NCI) | Started: 2004-03
PHASE1
NCT00019708
n=45
Extranodal Marginal Zone B-cell Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Non-Hodgkin Lymphoma
Interventions: tanespimycin
Sponsor: National Cancer Institute (NCI) | Started: 1999-06
PHASE1
NCT00319930
n=10
Chronic Lymphocytic Leukemia
Interventions: CNF1010 (17-AAG)
Sponsor: Biogen | Started: 2005-05
PHASE1
NCT00103272
n=74
Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia (M
Interventions: tanespimycin, bortezomib
Sponsor: National Cancer Institute (NCI) | Started: 2005-04