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Chiral Resolution and Pharmacological Characterization of the Enantiomers of the Hsp90 Inhibitor 2‐Amino‐7‐[4‐fluoro‐2‐(3‐pyridyl)phenyl]‐4‐methyl‐7,8‐dihydro‐6 H ‐quinazolin‐5‐one Oxime
Author(s) -
Amici Raffaella,
Bigogno Chiara,
Boggio Roberto,
Colombo Andrea,
Courtney Stephen M.,
Dal Zuffo Roberto,
Dondio Giulio,
Fusar Fulvia,
Gagliardi Stefania,
Minucci Saverio,
Molteni Marco,
Montalbetti Christian A. G. N.,
Mortoni Annalisa,
Varasi Mario,
Vultaggio Stefania,
Mercurio Ciro
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400037
Subject(s) - hsp90 , chemistry , enantiomer , hsp90 inhibitor , heat shock protein , stereochemistry , ic50 , bioavailability , biochemistry , amino acid , pharmacology , in vitro , biology , gene
Heat‐shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2‐Amino‐7‐[4‐fluoro‐2‐(3‐pyridyl)phenyl]‐4‐methyl‐7,8‐dihydro‐6 H ‐quinazolin‐5‐one oxime is a racemic Hsp90 inhibitor that targets the N‐terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The ( S ) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models.