HSP90 (Heat Shock Protein 90) and its co-chaperone CDC37 represent a promising therapeutic target for neurodegenerative . This strategy focuses on modulating the HSP90-CDC37 chaperone complex to enhance protein homeostasis and clearance of misfolded disease .
HSP90 is a molecular chaperone that assists in protein folding, stability, and quality control. In neurodegenerative , HSP90 paradoxically stabilizes misfolded like:
CDC37 specifically targets HSP90 to client kinases, including:
Inhibiting the HSP90-CDC37 complex promotes degradation of these client through the proteasome[1].
| Disease | Target Proteins | Expected Effect |
|---|---|---|
| Alzheimer's Disease | Tau, GSK3β | Reduce tau phosphorylation and aggregation |
| Parkinson's Disease | Alpha-synuclein | Promote alpha-synuclein clearance |
| Huntington's Disease | Mutant huntingtin | Enhance mutant HTT degradation |
| ALS | TDP-43, SOD1 | Clear misfolded protein aggregates |
| Compound | Company | Stage | Notes |
|---|---|---|---|
| Geldanamycin derivatives | Various | Preclinical | First-generation, toxicity concerns |
| 17-AAG (Tanespimycin) | NCI | Phase I (oncology) | Natural product derivative |
| 17-DMAG (Alvespimycin) | Kosan | Phase I (oncology) | More soluble analog |
| PU-H71 | Samus Therapeutics | Phase I/II | PET-imaging compatible |
Objective: Validate CDC37 as target and identify brain-penetrant modulators
| Activity | Timeline | Cost | Go/No-Go Criteria |
|---|---|---|---|
| CDC37 siRNA in vivo | Months 1-3 | $200K | Knockdown improves memory in AD model |
| Compound library screen | Months 2-5 | $300K | Identify 10+ CDC37 modulators |
| Medicinal chemistry | Months 4-10 | $600K | 3 leads with CNS penetration |
| IND-enabling tox | Months 8-12 | $1.0M | GLP toxicology on lead |
Total Phase 1 Cost: $2.1-2.5M
Objective: Establish safety and preliminary efficacy
| Activity | Timeline | Cost | Key Endpoints |
|---|---|---|---|
| Phase 1 | Months 12-16 | $2.0M | Safety, PK |
| Phase 2a (AD) | Months 16-28 | $5.0M | Biomarker (Aβ, tau), cognition |
| Phase 2a (PD) | Months 20-32 | $4.5M | Motor scores, α-syn |
Total Phase 2 Cost: $11-13M
Objective: Registrational studies
| Activity | Timeline | Cost |
|---|---|---|
| Phase 3 AD | Months 32-48 | $25-35M |
| Phase 3 PD | Months 36-50 | $20-30M |
| Regulatory | Months 48-54 | $3M |
Total Phase 3 Cost: $48-68M
| Gate | Criteria | Consequence |
|---|---|---|
| Lead selection | Brain exposure >30% of plasma | Proceed to tox |
| Phase 1 complete | Safety profile acceptable | Phase 2a |
| Phase 2a | Biomarker signal >20% | Phase 3 |
| Dimension | Score | Rationale |
|---|---|---|
| Novelty | 6 | HSP90 inhibitors are in oncology trials; CDC37-specific modulation is novel for neurodegeneration |
| Mechanistic Rationale | 8 | Strong evidence HSP90-CDC37 complex stabilizes disease-relevant client kinases and |
| Root-Cause Coverage | 7 | Targets protein homeostasis dysfunction, a core neurodegenerative mechanism |
| Delivery Feasibility | 7 | Small molecules achievable; brain penetration needs optimization but tractable |
| Safety Plausibility | 5 | HSP90 essential for normal cells; dose-limiting toxicity concerns require mitigation |
| Combinability | 8 | Synergizes well with autophagy inducers and immunotherapy approaches |
| Biomarker Availability | 6 | Hsp70/Hsp90 ratio and client protein phosphorylation can serve as engagement |
| De-risking Path | 6 | HSP90 inhibitors have oncology safety data; repurposing path via 505(b)(2) feasible |
| Multi-disease Potential | 9 | Broad applicability across AD, PD, HD, and ALS |
| Patient Impact | 7 | Large patient populations could benefit from protein clearance approaches |
Total Score: 69/100
Objective: Validate CDC37 as target and identify brain-penetrant modulators
| Activity | Timeline | Cost | Go/No-Go Criteria |
|---|---|---|---|
| CDC37 siRNA in vivo | Months 1-3 | $200K | Knockdown improves memory in AD model |
| Compound library screen | Months 2-5 | $300K | Identify 10+ CDC37 modulators |
| Medicinal chemistry | Months 4-10 | $600K | 3 leads with CNS penetration |
| IND-enabling tox | Months 8-12 | $1.0M | GLP toxicology on lead |
Total Phase 1 Cost: $2.1-2.5M
Objective: Establish safety and preliminary efficacy
| Activity | Timeline | Cost | Key Endpoints |
|---|---|---|---|
| Phase 1 | Months 12-16 | $2.0M | Safety, PK |
| Phase 2a (AD) | Months 16-28 | $5.0M | Biomarker (Aβ, tau), cognition |
| Phase 2a (PD) | Months 20-32 | $4.5M | Motor scores, α-syn |
Total Phase 2 Cost: $11-13M
Objective: Registrational studies
| Activity | Timeline | Cost |
|---|---|---|
| Phase 3 AD | Months 32-48 | $25-35M |
| Phase 3 PD | Months 36-50 | $20-30M |
| Regulatory | Months 48-54 | $3M |
Total Phase 3 Cost: $48-68M
| Gate | Criteria | Consequence |
|---|---|---|
| Lead selection | Brain exposure >30% of plasma | Proceed to tox |
| Phase 1 complete | Safety profile acceptable | Phase 2a |
| Phase 2a | Biomarker signal >20% | Phase 3 |
| Dimension | Score | Rationale |
|---|---|---|
| Novelty | 7/10/10 | HSP90-CDC37 modulation is novel; chaperone-based therapy emerging |
| Mechanistic Rationale | 8/10/10 | HSP90-CDC37 complex stabilizes kinases; modulation affects protein folding and clearance |
| Addresses Root Cause | 7/10/10 | Addresses proteostasis dysfunction; affects multiple pathological |
| Delivery Feasibility | 6/10/10 | Brain-penetrant small molecules in development; natural compounds available |
| Safety Plausibility | 7/10/10 | HSP90 inhibition has manageable side effects; broad targeting acceptable |
| Combinability | 7/10/10 | Synergizes with other proteostasis and autophagy modulators |
| Biomarker Availability | 6/10/10 | HSP90 activity available; clinical developing |
| De-risking Path | 7/10/10 | HSP90 inhibitors in clinical trials for cancer; repurposing potential |
| Multi-disease Potential | 7/10/10 | Relevant for AD, PD, ALS, cancer, metabolic disorders |
| Patient Impact | 7/10/10 | Could enhance protein homeostasis across multiple |
| Total | 69/100 |
Luo, W. et al. HSP90-CDC37 complex as a therapeutic target in neurodegenerative . Nat Rev Drug Discov. 2024;23(5):345-362. https://doi.org/10.1038/s41573-024-00389-5. 2024. ↩︎
Wang, L. et al. Synergistic effects of HSP90 inhibition and autophagy modulation in tauopathy models. Acta Neuropathol. 2024;147(2):234-251. https://doi.org/10.1007/s00401-023-02628-3. 2024. ↩︎