ID: hyp-SDA-2026-04-09-gap-debate-20260409-2
Hypothesis
Phosphorylation-State Dependent Inhibition
Inhibitors that selectively disrupt HSP90 machinery only when tau substrates are hyperphosphorylated, containing phosphoserine/threonine recognition domains conjugated to HSP90 pathway disruptors to create activity-based selectivity for .
drug discovery
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
Inhibitors that selectively disrupt HSP90 machinery only when tau substrates are hyperphosphorylated, containing phosphoserine/threonine recognition domains conjugated to HSP90 pathway disruptors to create activity-based selectivity for pathological tau species.
🧬 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.
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
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Volatility
High
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Events (7d)
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Price History
▲5.2%💾 Resource Usage
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Total Cost
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF PS19 tau P301S transgenic mice (8 months old, n≥10/group) with established tau pathology receive intraperitoneal injections of a phospho-tau selective HSP90 inhibitor (10 mg/kg) three times weekly | Hippocampal Sarkozyl-positive tau signal reduction ≥40% (p<0.01), with <15% change in total tau (Tau5 ELISA) | — no observation — | pending | 0.55 |
| IF phosphoserine/threonine recognition domain-HSP90 disruptor conjugates are applied to in vitro HSP90 complexes pre-incubated with hyperphosphorylated tau (p-tau Ser396/404) versus non-phosphorylated | IC50 ratio (non-phosphorylated/p-tau condition) ≥2.0, with >50% differential inhibition at 1 µM concentration | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF phosphoserine/threonine recognition domain-HSP90 disruptor conjugates are applied to in vitro HSP90 complexes pre-incubated with hyperphosphorylated tau (p-tau Ser396/404) versus non-phosphorylated recombinant tau, THEN p-tau-bound HSP90 activity will be inhibited at least 50% greater potency (lo
Predicted outcome: IC50 ratio (non-phosphorylated/p-tau condition) ≥2.0, with >50% differential inhibition at 1 µM concentration
Falsification: IC50 values differ by <1.2-fold between phosphorylated and non-phosphorylated tau conditions, indicating no phosphorylation-state selectivity
pendingconf 55%
IF PS19 tau P301S transgenic mice (8 months old, n≥10/group) with established tau pathology receive intraperitoneal injections of a phospho-tau selective HSP90 inhibitor (10 mg/kg) three times weekly for 4 weeks, THEN Sarko-positive/AT100-positive pathological tau species will decrease by ≥40% in hi
Predicted outcome: Hippocampal Sarkozyl-positive tau signal reduction ≥40% (p<0.01), with <15% change in total tau (Tau5 ELISA)
Falsification: Pathological tau reduction <20% OR total tau decreases proportionally (>25%), indicating loss of selectivity rather than activity-based targeting of phospho-dependent conformation
▸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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