title: An Hsp90 modulator that exhibits a unique mechanistic profile.
abstract: Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound-Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90. The macrocycle is similar in potency to other structurally-related analogs of Sansalvamide A (San A) and induces apoptosis via a caspase 3 mechanism. Unlike other San A derivatives, we show that the macrocycle does not inhibit binding between C-terminal client proteins and co-chaperones and Hsp90, suggesting that it has a unique mechanism of action.
authors.affiliation: Department of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Ramsey
authors.forename: Jeanette R
authors.initials: JR
authors.lastname: McConnell
authors.forename: Leslie D
authors.initials: LD
authors.lastname: Alexander
authors.forename: Kaishin W
authors.initials: KW
authors.lastname: Tanaka
authors.forename: Chester M
authors.initials: CM
authors.lastname: Vera
authors.forename: Shelli R
authors.initials: SR
authors.lastname: McAlpine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019921:Biotinylation; D053148:Caspase 3; D047630:Depsipeptides / Q000494:pharmacology; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects*; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D047630:Depsipeptides; D018841:HSP90 Heat-Shock Proteins; D047028:Macrocyclic Compounds; C119376:sansalvamide A; D053148:Caspase 3