title: Identification of novel HSP90α/β isoform selective inhibitors using structure-based drug design. demonstration of potential utility in treating CNS disorders such as Huntington's disease.
abstract: A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β 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 HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/β 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.
authors.affiliation: Vertex Pharmaceuticals , 11010 Torreyana Road, San Diego, California 92121, United States.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ernst
authors.forename: Timothy
authors.initials: T
authors.lastname: Neubert
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.forename: Samuel
authors.initials: S
authors.lastname: Sperry
authors.forename: Harmon
authors.initials: H
authors.lastname: Zuccola
authors.forename: Amy
authors.initials: A
authors.lastname: Turnbull
authors.forename: Beth
authors.initials: B
authors.lastname: Fleck
authors.forename: William
authors.initials: W
authors.lastname: Kargo
authors.forename: Lisa
authors.initials: L
authors.lastname: Woody
authors.forename: Peggy
authors.initials: P
authors.lastname: Chiang
authors.forename: Dao
authors.initials: D
authors.lastname: Tran
authors.forename: Weichao
authors.initials: W
authors.lastname: Chen
authors.forename: Phillip
authors.initials: P
authors.lastname: Snyder
authors.forename: Timothy
authors.initials: T
authors.lastname: Alcacio
authors.forename: Azin
authors.initials: A
authors.lastname: Nezami
authors.forename: James
authors.initials: J
authors.lastname: Reynolds
authors.forename: Khisal
authors.initials: K
authors.lastname: Alvi
authors.forename: Lance
authors.initials: L
authors.lastname: Goulet
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
mesh_terms: D000818:Animals; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; C493165:HSP90AB1 protein, human