4O05: Identification of novel HSP90/isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90alpha/beta inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90alpha/beta inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90alpha/beta selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90alpha/beta inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.
PDB ID: 4O05Download
MMDB ID: 119055
PDB Deposition Date: 2013/12/13
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 1.79  Å
Source Organism:
Similar Structures:
Biological Unit for 4O05: monomeric; determined by author and by software (PISA)
Molecular Components in 4O05
Label Count Molecule
Protein (1 molecule)
Heat Shock Protein HSP 90-alpha(Gene symbol: HSP90AA1)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB