Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity-Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases

Justin T Ernst; Michael Liu; Harmon Zuccola; Timothy Neubert; Kevin Beaumont; Amy Turnbull; Adam Kallel; Bryan Vought; Dean Stamos

doi:10.1016/j.bmcl.2013.11.036

Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity-Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases

Bioorg Med Chem Lett. 2014 Jan 1;24(1):204-8. doi: 10.1016/j.bmcl.2013.11.036. Epub 2013 Nov 23.

Authors

Justin T Ernst¹, Michael Liu², Harmon Zuccola³, Timothy Neubert⁴, Kevin Beaumont², Amy Turnbull², Adam Kallel⁴, Bryan Vought³, Dean Stamos⁴

Affiliations

¹ Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: Justin_Ernst@vrtx.com.
² Vertex Pharmaceuticals, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
³ Vertex Pharmaceuticals, Department of Protein Sciences, 130 Waverly Street, Cambridge, MA 02139, United States.
⁴ Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.

PMID: 24332488
DOI: 10.1016/j.bmcl.2013.11.036

Abstract

HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and β is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/β appear to strongly influence isoform selectivity. The rational design of HSP90α/β inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.

Keywords: GRP94; HSP90 inhibitors; Huntingtin; Huntington’s disease; Isoform selectivity; Structure-based drug design; TRAP1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Crystallography, X-Ray
Drug Design*
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Models, Molecular
Molecular Structure
Neurodegenerative Diseases / drug therapy*
Protein Isoforms / antagonists & inhibitors

Substances

HSP90 Heat-Shock Proteins
Protein Isoforms