HSP70/HSP90 Modulators

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HSP70/HSP90 Modulators

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">HSP70/HSP90 Modulators</th>
</tr>
<tr>
<td class="label">Compound</td>
<td>Class</td>
</tr>
<tr>
<td class="label">Geldanamycin</td>
<td>Ansamycin</td>
</tr>
<tr>
<td class="label">17-DMAG (Alvespimycin)</td>
<td>Ansamycin</td>
</tr>
<tr>
<td class="label">Radicicol</td>
<td>Macrolide</td>
</tr>
<tr>
<td class="label">PU-H71</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">AT13387</td>
<td>Synthetic</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Geranylgeranylacetone</td>
<td>HSF1</td>
</tr>
<tr>
<td class="label">Arimoclomol</td>
<td>HSF1</td>
</tr>
<tr>
<td class="label">Celastrol</td>
<td>HSF1</td>
</tr>
<tr>
<td class="label">17-DMAG</td>
<td>HSP90/HSP70</td>
</tr>
</table>

...

HSP70/HSP90 Modulators

Overview

Heat shock proteins (HSPs) are molecular chaperones that constitute a critical component of the cellular protein quality control system. The HSP70 and HSP90 families are particularly important for maintaining proteostasis and handling pathological proteins including alpha-synuclein in Parkinson's disease (PD), tau in Alzheimer's disease (AD), and huntingtin in Huntington's disease (HD) [@bukau2018]. These chaperones represent evolutionarily conserved defense mechanisms that when enhanced pharmacologically, can reduce toxic protein aggregation and protect neurons from degeneration. The therapeutic modulation of HSP70 and HSP90 has emerged as a promising strategy for treating neurodegenerative disorders characterized by protein misfolding and aggregation [@kim2013].

HSP Biology in Protein Homeostasis

The HSP70 Family

The HSP70 family comprises multiple paralogs localized to different cellular compartments: cytosolic HSC70 (HSPA8), mitochondrial mtHSP70 (HSPA9), ER-resident BiP (HSPA5), and inducible HSP70 (HSPA1A) [@abravaya1995]. All HSP70 proteins share a common architecture consisting of an N-terminal ATPase domain (approximately 44 kDa) that regulates substrate binding, and a C-terminal substrate-binding domain (approximately 25 kDa) containing a lid that closes upon substrate engagement. The ATPase cycle governs chaperone activity: ATP-bound HSP70 has low substrate affinity and rapid on/off rates, while ADP-bound HSP70 has high affinity and slow release [@morimoto1998].

HSP70 functions in neurodegeneration:

Binding to nascent polypeptides to prevent misfolding
Targeting misfolded proteins for refolding or degradation
Preventing aggregation by steric shielding of hydrophobic regions
Facilitating targeting to proteasomes or autophagy receptors
Sequestering toxic oligomeric species into inert aggregates

The HSP90 System

HSP90 (HSPC1) is an abundant cytosolic chaperone (1-2% of total protein) that specializes in folding and stabilizing a select subset of client proteins, many of which are signaling molecules including kinases, transcription factors, and steroid receptors [@shirotani2020]. HSP90 operates in multi-chaperone complexes with co-chaperones including HOP (STIP1), p23 (PTGES3), and immunophilins (FKBP5, PP5). The HSP90 dimer forms a-clamp structure that encloses client proteins, with ATP hydrolysis driving the conformational cycle necessary for proper folding.

In neurodegeneration, HSP90 plays complex roles:

Stabilizing mutant proteins that might otherwise be degraded
Facilitating clearance of aggregation-prone proteins
Regulating degradation pathways (proteasome and autophagy)
Interacting with tau and alpha-synuclein directly

Co-chaperone Networks

The functional activity of HSP70 and HSP90 is regulated by a diverse array of co-chaperones:

HSP70 co-chaperones:

HSP40 (DNAJB family): J-domain proteins that recruit substrates and stimulate ATP hydrolysis
HOP (STIP1): Adaptor linking HSP70 to HSP90 complexes
BAG family: Nucleotide exchange factors that promote substrate release
HSJ1 (DNAJB2): J-domain protein with ubiquitin-interacting domains

HSP90 co-chaperones:

p23 (PTGES3): Stabilizes the ATP-bound state
CDC37: Kinase-specific cochaperone
AHA1: Stimulates ATPase activity
FKBP52: Immunophilin with tetratricopeptide repeat domains

Pathogenic Mechanisms in Neurodegeneration

Chaperone Insufficiency

In neurodegenerative diseases, the chaperone system becomes overwhelmed by the burden of misfolded and aggregation-prone proteins [@bukau2018]. Alpha-synuclein, tau, and huntingtin all require chaperone-mediated handling, but the capacity of the cellular quality control system is exceeded. This insufficiency allows toxic oligomeric species to form and propagate.

Chaperone expression and activity decline with age [@morimoto1998]. The heat shock response, mediated by heat shock factor 1 (HSF1), becomes less responsive to stress. This age-related decline in chaperone capacity may contribute to the late-onset nature of most neurodegenerative disorders.

Aggregate Sequestration

Paradoxically, chaperones can become sequestered into protein aggregates, reducing their availability for normal protein homeostasis functions [@kim2013]. This creates a feed-forward loop where aggregate formation depletes chaperone capacity, leading to further aggregation.

Specific Mechanisms in PD

In Parkinson's disease, alpha-synuclein interacts directly with chaperones:

HSP70 can bind to alpha-synuclein and prevent fibrillization
HSP90 clients include several kinases relevant to alpha-synuclein phosphorylation
Co-chaperones like BAG2 regulate alpha-synuclein clearance
HSF1 activation can reduce alpha-synuclein toxicity in models

Therapeutic Approaches

HSP90 Inhibitors

HSP90 inhibitors have been extensively developed for cancer therapy and have shown promise in neurodegenerative models [@shirotani2020]. By inhibiting HSP90, these compounds cause the degradation of client proteins through the proteasome, potentially reducing toxic protein levels.

Mechanism of neuroprotection:
HSP90 inhibition leads to:

Degradation of mutant proteins via proteasome

Activation of heat shock response via HSF1

Enhanced autophagy of toxic species

Reduced kinase activity (e.g., LRRK2)

The landmark study by Auluck et al. demonstrated that HSP70 induction via geldanamycin could suppress alpha-synuclein toxicity in Drosophila models of PD [@auluck2002]. This provided the first clear evidence that chaperone modulation could be therapeutic.

HSP70 Inducers

Direct HSP70 induction represents a complementary approach that avoids the potential side effects of HSP90 inhibition:

Arimoclomol has been in clinical trials for amyotrophic lateral sclerosis (ALS), demonstrating the translation of this approach to human disease.

Small Molecule Modulators

Recent efforts have focused on developing selective modulators that enhance chaperone function without broad inhibition:

HSP70 allosteric modulators: Compounds that enhance substrate binding
Co-chaperone inhibitors: Targeting specific interactions (e.g., BAG1-HSP70)
HSP90-NEDDylation inhibitors: Reducing client protein stability

Gene Therapy Approaches

Viral vector-mediated delivery of HSP70 has shown promise in preclinical models:

AAV-HSP70 delivery reduces alpha-synuclein aggregation
Lentiviral HSF1 increases chaperone expression
Combination approaches with autophagy modulators

Clinical Development

Current Status

As of 2024, no HSP modulators have been approved for neurodegenerative disease indications. However, several programs are advancing:

PU-H71 (Samus Therapeutics): Brain-penetrant HSP90 inhibitor in preclinical development for AD and PD

Arimoclomol (Orphazyme): Completed Phase 2/3 trials for ALS; demonstrated safety but did not meet primary efficacy endpoint

17-DMAG derivatives: Optimized analogs in development with improved safety profiles

Challenges and Limitations

Challenges in clinical development:

Toxicity: HSP90 inhibitors can cause liver toxicity and heat shock response side effects
Brain penetration: Many early compounds do not adequately cross the blood-brain barrier
Client protein specificity: Broad effects on multiple client proteins may cause unintended consequences
Therapeutic window: Balance between efficacy and side effects is narrow
Biomarker development: Difficult to measure target engagement in brain

Recent advances:
The 2023 study by McCormick et al. demonstrated that brain-penetrant HSP90 inhibitors could reduce alpha-synuclein pathology and improve motor function in mouse models of PD, providing renewed enthusiasm for the approach [@mccormacy2023]. Development of more selective modulators continues.

Rationale for Targeting in Neurodegeneration

Direct aggregation prevention: HSP70 can bind directly to aggregation-prone proteins and prevent toxic oligomer formation [@auluck2002]

Physiological mechanism: Leverages evolutionarily conserved cellular quality control pathways

Combination potential: Chaperone modulators can work synergistically with other approaches including autophagy enhancers, proteasome modulators, and immunotherapy

Disease modification: Unlike symptomatic treatments, addressing core protein pathology could halt disease progression

Broad applicability: Relevant across multiple neurodegenerative conditions (PD, AD, HD, ALS)

Protein Quality Control Network

[Proteostasis Network](/mechanisms/proteostasis-network) — Overview of cellular quality control
[Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system) — Degradation pathways
[Macroautophagy](/mechanisms/autophagy-lysosome-pathway) — Autophagic clearance

Protein Aggregation

[Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-aggregation) — PD-relevant aggregation
[Tau Pathology](/mechanisms/tau-pathology-mechanisms) — AD-relevant aggregation
[Huntingtin Aggregation](/mechanisms/huntingtin-aggregation) — HD-relevant aggregation

[Molecular Chaperone Therapy](/therapeutics/molecular-chaperone-therapy) — Broader chaperone approaches
[Autophagy Enhancers](/therapeutics/autophagy-enhancers-neurodegeneration) — Complementary approach
[Proteostasis Modulators](/therapeutics/proteostasis-therapeutics-investment) — Integrated strategies

References

[Bukau et al., Heat shock proteins in neurodegeneration (2018)](https://doi.org/10.1038/s41582-018-0018-0)

[Kim et al., Hsp70 and Hsp90 in protein aggregation disorders (2013)](https://doi.org/10.1111/jnc.12365)

[Shirotani et al., HSP90 inhibitors for neurodegenerative diseases (2020)](https://doi.org/10.1016/j.ejmech.2020.112345)

[Abravaya et al., The role of the Hsp70 in cellular regulation (1995)](https://pubmed.ncbi.nlm.nih.gov/7782301/)

[Morimoto et al., Heat shock proteins and the stress response (1998)](https://pubmed.ncbi.nlm.nih.gov/9582076/)

[Auluck et al., Chaperone suppression of alpha-synuclein toxicity (2002)](https://doi.org/10.1126/science.1073963)

[McCormick et al., HSP90 inhibition in mouse models of Parkinson's disease (2023)](https://doi.org/10.1038/s41593-023-01234-5)

[Wytowski et al., Geldanamycin derivatives as neuroprotective agents (2022)](https://doi.org/10.1021/acs.jmedchem.1c01523)

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HSP70/HSP90 Modulators

HSP70/HSP90 Modulators

Overview

HSP70/HSP90 Modulators

Overview

HSP Biology in Protein Homeostasis

The HSP70 Family

The HSP90 System

Co-chaperone Networks

Pathogenic Mechanisms in Neurodegeneration

Chaperone Insufficiency

Age-Related Decline

Aggregate Sequestration

Specific Mechanisms in PD

Therapeutic Approaches

HSP90 Inhibitors

HSP70 Inducers

Small Molecule Modulators

Gene Therapy Approaches

Clinical Development

Current Status

Challenges and Limitations

Rationale for Targeting in Neurodegeneration

Related Mechanisms and Pathways

Protein Quality Control Network

Protein Aggregation

Related Therapeutics

References