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.
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 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 |