ID: hyp-SDA-2026-04-09-gap-debate-20260409-2
Hypothesis
Competitive Co-chaperone Displacement
Small molecules that competitively displace tau-stabilizing immunophilins (FKBP51) from HSP90 while recruiting tau-destabilizing co-chaperones (FKBP52), reprogramming HSP90 complexes from tau-protective to tau-degrading without inhibitin.
drug discovery
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Small molecules that competitively displace tau-stabilizing immunophilins (FKBP51) from HSP90 while recruiting tau-destabilizing co-chaperones (FKBP52), reprogramming HSP90 complexes from tau-protective to tau-degrading without inhibiting HSP90's essential functions.
🧬 Mechanism
🔗 Mechanism from KG for FKBP5
Auto-built from this analysis's top knowledge-graph edges.
graph TD
FKBP5["FKBP5"] -->|protein interactio| HSP90AA1["HSP90AA1"]
FKBP51["FKBP51"] -->|stabilizes| tau["tau"]
FKBP52["FKBP52"] -->|destabilizes| tau_1["tau"]
SAFit_compounds["SAFit compounds"] -->|targets| FKBP5_2["FKBP5"]
FKBP5_3["FKBP5"] -->|protective against| tau_protein_aggregation["tau protein aggregation"]
FKBP51_4["FKBP51"] -.->|inhibits| HSP90AA1_5["HSP90AA1"]
style FKBP5 fill:#ce93d8,stroke:#333,color:#000
style HSP90AA1 fill:#ce93d8,stroke:#333,color:#000
style FKBP51 fill:#4fc3f7,stroke:#333,color:#000
style tau fill:#4fc3f7,stroke:#333,color:#000
style FKBP52 fill:#4fc3f7,stroke:#333,color:#000
style tau_1 fill:#4fc3f7,stroke:#333,color:#000
style SAFit_compounds fill:#4fc3f7,stroke:#333,color:#000
style FKBP5_2 fill:#4fc3f7,stroke:#333,color:#000
style FKBP5_3 fill:#ce93d8,stroke:#333,color:#000
style tau_protein_aggregation fill:#4fc3f7,stroke:#333,color:#000
style FKBP51_4 fill:#4fc3f7,stroke:#333,color:#000
style HSP90AA1_5 fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.
Supports
Interplay of p23 with FKBP51 and their chaperone complex in regulating tau aggregation.
Supports
The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules.
Supports
Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases.
Supports
Organization and function of the FKBP52 and FKBP51 genes.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — FKBP5
No curated PDB or AlphaFold mapping for FKBP5 yet. Search RCSB →
💉 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 FKBP5.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▲ 0.0%
Volatility
High
0.0511
Events (7d)
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Price History
▲5.2%💾 Resource Usage
LLM Tokens
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$0.1124
Total Cost
$0.1124
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived cortical neurons harboring P301L MAPT mutations are treated with a 100 nM concentration of a small molecule designed to competitively displace FKBP51 from HSP90 while preferentia | Soluble tau concentration will decrease by at least 40% in compound-treated neurons compared to vehicle control at 72 hours post-treatment. | — no observation — | pending | 0.65 |
| IF male 3xTg-AD mice (6 months old) receive daily intraperitoneal injections of a selective FKBP51-displacing/FKBP52-recruiting compound at 10 mg/kg for 28 days, THEN hippocampal insoluble tau aggrega | Sarkosyl-insoluble tau will be at least 35% lower in compound-treated 3xTg-AD mice relative to vehicle controls after 4 weeks of treatment. | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF human iPSC-derived cortical neurons harboring P301L MAPT mutations are treated with a 100 nM concentration of a small molecule designed to competitively displace FKBP51 from HSP90 while preferentially recruiting FKBP52, THEN intracellular soluble tau levels will decrease by ≥40% relative to vehic
Predicted outcome: Soluble tau concentration will decrease by at least 40% in compound-treated neurons compared to vehicle control at 72 hours post-treatment.
Falsification: Soluble tau levels do not decrease by at least 40% (e.g., <25% change) or show no significant difference from vehicle control (p > 0.05, Student's t-test), indicating the co-chaperone displacement mec
pendingconf 55%
IF male 3xTg-AD mice (6 months old) receive daily intraperitoneal injections of a selective FKBP51-displacing/FKBP52-recruiting compound at 10 mg/kg for 28 days, THEN hippocampal insoluble tau aggregates will be reduced by ≥35% compared to vehicle-injected age-matched controls, as measured by Sarkos
Predicted outcome: Sarkosyl-insoluble tau will be at least 35% lower in compound-treated 3xTg-AD mice relative to vehicle controls after 4 weeks of treatment.
Falsification: No significant reduction in Sarkosyl-insoluble tau (<20% change) or reduction accompanied by motor impairment, weight loss, or hunching behavior indicating HSP90 essential function inhibition (disqual
▸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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