title: Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90.
abstract: Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for activating many signaling proteins and is a promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic studies show that these compounds bind in the ATP binding pocket interacting with the Asp93. Structure based optimization led to the identification of potent analogues, such as 13, with good biochemical profiles.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. gopalsa@wyeth.com
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Golas
authors.forename: Erik
authors.initials: E
authors.lastname: Vogan
authors.forename: Jaison
authors.initials: J
authors.lastname: Jacob
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Frederick
authors.initials: F
authors.lastname: Lee
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Nilakantan
authors.forename: Roseann
authors.initials: R
authors.lastname: Petersen
authors.forename: Kristin
authors.initials: K
authors.lastname: Svenson
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: May S
authors.initials: MS
authors.lastname: Tam
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Wen
authors.forename: John
authors.initials: J
authors.lastname: Ellingboe
authors.forename: Kim
authors.initials: K
authors.lastname: Arndt
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020014:K562 Cells; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D000255:Adenosine Triphosphate