title: 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.
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.
authors: Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: Justin_Ernst@vrtx.com.
authors: Justin T
authors: JT
authors: Ernst
authors: Vertex Pharmaceuticals, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Michael
authors: M
authors: Liu
authors: Vertex Pharmaceuticals, Department of Protein Sciences, 130 Waverly Street, Cambridge, MA 02139, United States.
authors: Harmon
authors: H
authors: Zuccola
authors: Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Timothy
authors: T
authors: Neubert
authors: Vertex Pharmaceuticals, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Kevin
authors: K
authors: Beaumont
authors: Vertex Pharmaceuticals, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Amy
authors: A
authors: Turnbull
authors: Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Adam
authors: A
authors: Kallel
authors: Vertex Pharmaceuticals, Department of Protein Sciences, 130 Waverly Street, Cambridge, MA 02139, United States.
authors: Bryan
authors: B
authors: Vought
authors: Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Dean
authors: D
authors: Stamos
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors
chemical_list: D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms
keywords: GRP94; HSP90 inhibitors; Huntingtin; Huntington’s disease; Isoform selectivity; Structure-based drug design; TRAP1