ID: hyp-SDA-2026-04-09-gap-debate-20260409-2
Hypothesis
Allosteric Pocket Exploitation for Tau-Specific HSP90 Modulation
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 p.
drug discovery
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
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.
🧬 Mechanism
🔗 Mechanism from KG for HSP90AA1
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:#000⚖️ Evidence
⚖️ Evidence Matrix5 supports2 contradicts
Supports
Folding or holding?-Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease.
Supports
Hsp90-interacting Co-chaperones and their Family Proteins in Tau Regulation: Introducing a Novel Role for Cdc37L1.
Supports
The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules.
Supports
To fold or not to fold: modulation and consequences of Hsp90 inhibition.
Supports
Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice.
Contradicts
Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis.
Contradicts
Mapping the pathogenic nexus: Gene overlap and protein interaction networks in Alzheimer's and breast cancer as a precursor to protein structure prediction and analysis.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — HSP90AA1
💉 Clinical Trials
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.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▲ 0.0%
Volatility
High
0.0511
Events (7d)
0
Price History
▲5.2%💾 Resource Usage
LLM Tokens
18,738
$0.1124
Total Cost
$0.1124
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| 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 |
🔮 Falsifiable Predictions (2)
pendingconf 70%
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 will be observed relative to vehicle‑treated mice within 2 weeks after the final dose.
Predicted outcome: Brain detergent‑soluble tau concentration (ELISA) decreases by ≥30 % versus vehicle control.
Falsification: No significant reduction in tau levels (≤10 % change) or concurrent alteration of known HSP90 client proteins (e.g., AKT, ERK) by >20 %.
pendingconf 65%
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 to DMSO control, while total HSP90 ATPase activity remains unchanged (±10 %).
Predicted outcome: Co‑IP densitometry shows ≥50 % decrease in tau‑HSP90 complex; HSP90 ATPase assay shows no >10 % inhibition.
Falsification: No change in tau‑HSP90 interaction (≤20 % reduction) or significant inhibition of HSP90 ATPase activity (>30 % decrease).
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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