Phosphorylation-State Dependent Inhibition

Mechanistic description

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 / pathway

HSP90AA1
→
drug discovery

Evidence for (5)

Folding or holding?-Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease.

PMID:35398094 2022 J Biol Chem
Hsp90-interacting Co-chaperones and their Family Proteins in Tau Regulation: Introducing a Novel Role for Cdc37L1.

PMID:33246057 2021 Neuroscience
The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules.

PMID:20071522 2010 J Neurosci
To fold or not to fold: modulation and consequences of Hsp90 inhibition.

PMID:20161407 2009 Future Med Chem
Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice.

PMID:33832539 2021 Acta Neuropathol Commun

Evidence against (2)

Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis.

PMID:36180911 2022 BMC Complement Med Ther
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.

PMID:40973403 2025 Adv Protein Chem Struct Biol

Evidence matrix

5 supporting 2 contradicting

71% supporting

Supporting

Folding or holding?-Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease. PMID:35398094 · 2022 · J Biol Chem
Hsp90-interacting Co-chaperones and their Family Proteins in Tau Regulation: Introducing a Novel Role for Cdc37L1. PMID:33246057 · 2021 · Neuroscience
The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules. PMID:20071522 · 2010 · J Neurosci
To fold or not to fold: modulation and consequences of Hsp90 inhibition. PMID:20161407 · 2009 · Future Med Chem
Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice. PMID:33832539 · 2021 · Acta Neuropathol Commun

Contradicting

Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis. PMID:36180911 · 2022 · BMC Complement Med Ther
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. PMID:40973403 · 2025 · Adv Protein Chem Struct Biol

Cite this hypothesis

Citation

etl-backfill (2026). Phosphorylation-State Dependent Inhibition. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/hyp-SDA-2026-04-09-gap-debate-20260409-201742-5407d57d-6

BibTeX

@misc{scidex_hypothesis_hypsda20,
  title        = {Phosphorylation-State Dependent Inhibition},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/hyp-SDA-2026-04-09-gap-debate-20260409-201742-5407d57d-6},
  note         = {SciDEX artifact hypothesis:hyp-SDA-2026-04-09-gap-debate-20260409-201742-5407d57d-6}
}