Allosteric modulators targeting cryptic sites in HSP90's C-terminal domain that are uniquely accessible when HSP90 is bound to tau-containing complexes, selectively destabilizing tau-HSP90 interactions while preserving essential client protein folding.
Auto-built from this analysis's top knowledge-graph edges.
graph TD
HSP90AA1["HSP90AA1"] -->|participates in| protein_folding["protein_folding"]
FKBP5["FKBP5"] -->|protein interactio| HSP90AA1_1["HSP90AA1"]
FKBP4["FKBP4"] -->|protein interactio| HSP90AA1_2["HSP90AA1"]
MAPT["MAPT"] -->|regulates| HSP90AA1_3["HSP90AA1"]
HSP90AA1_4["HSP90AA1"] -->|regulates| tau_protein["tau protein"]
FKBP51["FKBP51"] -.->|inhibits| HSP90AA1_5["HSP90AA1"]
Ganetespib["Ganetespib"] -.->|inhibits| HSP90AA1_6["HSP90AA1"]
n17_AAG["17-AAG"] -.->|inhibits| HSP90AA1_7["HSP90AA1"]
HSP90AA1_8["HSP90AA1"] -->|regulates| tau_HSP90_interactions["tau-HSP90 interactions"]
Co_chaperones["Co-chaperones"] -->|modulates| HSP90AA1_function["HSP90AA1 function"]
HSP90AA1_9["HSP90AA1"] -->|regulates| proteasomal_degradation_p["proteasomal degradation pathway"]
HSP90AA1_C_terminal_domai["HSP90AA1 C-terminal domain"] -->|regulates| tau_HSP90_complex_formati["tau-HSP90 complex formation"]
style HSP90AA1 fill:#ce93d8,stroke:#333,color:#000
style protein_folding fill:#81c784,stroke:#333,color:#000
style FKBP5 fill:#ce93d8,stroke:#333,color:#000
style HSP90AA1_1 fill:#ce93d8,stroke:#333,color:#000
style FKBP4 fill:#ce93d8,stroke:#333,color:#000
style HSP90AA1_2 fill:#ce93d8,stroke:#333,color:#000
style MAPT fill:#ce93d8,stroke:#333,color:#000
style HSP90AA1_3 fill:#ce93d8,stroke:#333,color:#000
style HSP90AA1_4 fill:#4fc3f7,stroke:#333,color:#000
style tau_protein fill:#4fc3f7,stroke:#333,color:#000
style FKBP51 fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_5 fill:#4fc3f7,stroke:#333,color:#000
style Ganetespib fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_6 fill:#4fc3f7,stroke:#333,color:#000
style n17_AAG fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_7 fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_8 fill:#4fc3f7,stroke:#333,color:#000
style tau_HSP90_interactions fill:#4fc3f7,stroke:#333,color:#000
style Co_chaperones fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_function fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_9 fill:#4fc3f7,stroke:#333,color:#000
style proteasomal_degradation_p fill:#81c784,stroke:#333,color:#000
style HSP90AA1_C_terminal_domai fill:#4fc3f7,stroke:#333,color:#000
style tau_HSP90_complex_formati fill:#4fc3f7,stroke:#333,color:#000No linked papers recorded for this hypothesis yet.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for HSP90AA1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF P301S transgenic mice are treated daily with an allosteric HSP90 modulator (e.g., compound SDA-001) at 10 mg/kg for 28 days, THEN a ≥30% reduction in detergent‑soluble tau levels in brain tissue wi | Brain detergent‑soluble tau concentration (ELISA) decreases by ≥30 % versus vehicle control. | — no observation — | pending | 0.70 |
| IF human iPSC‑derived cortical neurons overexpressing 2N4R tau are treated with 1 µM of the allosteric HSP90 modulator for 48 h, THEN tau‑HSP90 co‑immunoprecipitation will be reduced by ≥50 % relative | Co‑IP densitometry shows ≥50 % decrease in tau‑HSP90 complex; HSP90 ATPase assay shows no >10 % inhibition. | — no observation — | pending | 0.65 |