title: 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-6H-quinazolin-5-one oxime.
abstract: 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-6H-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.
authors.affiliation: Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milan (Italy); Current address: Drug Discovery Program, Department of Experimental Oncology, IEO-European Institute of Oncology, Via Adamello 16, 20139 Milan (Italy). raffaella.amici@ieo.eu.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Amici
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.forename: Andrea
authors.initials: A
authors.lastname: Colombo
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Courtney
authors.forename: Roberto
authors.initials: R
authors.lastname: Dal Zuffo
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Fulvia
authors.initials: F
authors.lastname: Fusar
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Marco
authors.initials: M
authors.lastname: Molteni
authors.forename: Christian A G N
authors.initials: CA
authors.lastname: Montalbetti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mortoni
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Stefania
authors.initials: S
authors.lastname: Vultaggio
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D052999:Quinazolinones / Q000737:chemistry*; D013237:Stereoisomerism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D010091:Oximes; D052999:Quinazolinones
keywords: Hsp90; antitumor agents; chiral resolution; enantiomers; oximes