HSPA1A

Heat Shock Protein Family A Member 1A

Score: 0.643 Price: $0.64 Medium Druggability Status: active Wiki: HSPA1A

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

632

DEBATES

3D Protein Structure

🧬 HSPA1A — PDB 3GDQ Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.46

Clinical Stage

Phase III

Target Class

Chaperone

Safety

0.60

Druggability Analysis

Drug Development0.55

Structural Tractability0.95

Target Class0.50

Safety Profile0.60

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (3 compounds)

2 Phase III · 1 Preclinical

Therapeutic Areas:

Neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's) Protein misfolding disorders (prion diseases, amyloidosis) Cancer (HSP70 inhibition as oncology strategy) Ischemic neuroprotection Spinal muscular atrophy (SMA)

Druggability Rationale: HSPA1A demonstrates medium druggability (0.60) supported by 60 PDB structures with excellent resolution (1.34 Å), multiple phase 3 clinical candidates (17-AAG, Ganetespib), and a well-characterized ATP-binding pocket. However, the challenge lies in achieving selective modulation of chaperone function without triggering unwanted stress responses, and the target's highly conserved nature across HSP70 family members complicates isoform selectivity.

Mechanism: Small molecule activators or allosteric modulators of chaperone function

Drug Pipeline (3 compounds)

2 Phase III · 1 Preclinical

Known Drugs:

17-AAG (phase_3) — cancer

Ganetespib (phase_3) — cancer

VER-155008 (research_tool) — cancer research

Structural Data:

PDB (60) ✓AlphaFold ✓Cryo-EM ✓

1S3X 2LMG 3ATU 3ATV 3AY9+55 more

UniProt: V9GZ37

Binding Pocket Analysis:

HSPA1A contains a canonical ATP-binding site in the nucleotide-binding domain (NBD) that has been extensively targeted by HSP90 inhibitors like 17-AAG, as well as allosteric pockets amenable to small molecule modulators that enhance chaperone-substrate binding without direct nucleotide displacement. Structural data reveals multiple potential allosteric sites suitable for selective activators.

🧬 3D Protein Structure

🧬 HSPA1A — PDB 3GDQ Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

Selectivity remains a significant challenge due to high sequence homology among HSP70 isoforms (HSPA1A, HSPA1B, HSPA2); off-target engagement with other heat shock proteins and potential immune activation through stress response pathways must be carefully managed. Allosteric modulation strategies may offer better selectivity than direct ATP-site inhibitors.