Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90.
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.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. gopalsa@wyeth.com
Shi
Mengxiao
M
Golas
Jennifer
J
Vogan
Erik
E
Jacob
Jaison
J
Johnson
Mark
M
Lee
Frederick
F
Nilakantan
Ramaswamy
R
Petersen
Roseann
R
Svenson
Kristin
K
Chopra
Rajiv
R
Tam
May S
MS
Wen
Yingxia
Y
Ellingboe
John
J
Arndt
Kim
K
Boschelli
Frank
F
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
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D000255:Adenosine Triphosphate