title: Synthesis and biological evaluation of a new class of geldanamycin derivatives as potent inhibitors of Hsp90.
abstract: The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt followed by their proteasomal degradation. Hsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage for cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and ureas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.
authors.affiliation: Conforma Therapeutics Corporation, Suite 240, San Diego, CA 92121, USA. jlebrazidec@conformacorp.com
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Brazidec
authors.forename: Adeela
authors.initials: A
authors.lastname: Kamal
authors.forename: David
authors.initials: D
authors.lastname: Busch
authors.forename: Lia
authors.initials: L
authors.lastname: Thao
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Gregg
authors.initials: G
authors.lastname: Timony
authors.forename: Roy
authors.initials: R
authors.lastname: Grecko
authors.forename: Katy
authors.initials: K
authors.lastname: Trent
authors.forename: Rachel
authors.initials: R
authors.lastname: Lough
authors.forename: Tim
authors.initials: T
authors.lastname: Salazar
authors.forename: Samina
authors.initials: S
authors.lastname: Khan
authors.forename: Francis
authors.initials: F
authors.lastname: Burrows
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016227:Benzoquinones; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D047029:Lactams, Macrocyclic; D051379:Mice; D008807:Mice, Inbred BALB C; D011487:Protein Conformation; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C001277:geldanamycin