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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‐6H‐quinazolin‐5‐one Oxime |
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| Authors: | Dr Raffaella Amici Dr Chiara Bigogno Dr Roberto Boggio Dr Andrea Colombo Dr Stephen M Courtney Dr Roberto Dal Zuffo Dr Giulio Dondio Dr Fulvia Fusar Dr Stefania Gagliardi Prof Dr Saverio Minucci Dr Marco Molteni Dr Christian A G N Montalbetti Dr Annalisa Mortoni Dr Mario Varasi Dr Stefania Vultaggio Dr Ciro Mercurio |
| Affiliation: | 1. Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milan (Italy);2. Current address: Drug Discovery Program, Department of Experimental Oncology, IEO‐European Institute of Oncology, Via Adamello 16, 20139 Milan (Italy);3. NiKem Research s.r.l., Via Zambeletti 25, 20021 Baranzate (Italy);4. Current address: Aphad s.r.l. Via della Resistenza 65, 20090 Buccinasco (MI) (Italy);5. Current address: IRBM Promidis s.r.l. Via Pontina km 30, 600, 00040 Pomezia (RM) (Italy);6. Current address: Teva Pharmaceuticals Fine Chemicals, Strada Statale Briantea, 23892 Bulciago (Italy);7. Evotec, 114 Milton Park, Abingdon, Oxfordshire, OX10 4SA (UK);8. Genextra Group, DAC s.r.l., Via Adamello 16, 20139 Milan (Italy);9. Current address: Flamma S.p.A. Via Bedeschi 22, 24040 Chignolo d'Isola (BG) (Italy);10. IEO–European Institute of Oncology, Via Adamello 16, 20139 Milan (Italy);11. Department of Life Sciences, University of Milan, Via Celoria 26, 20133 Milan (Italy);12. Current address: Chorisis s.r.l. Via R. Lepetit 34, 21040 Gerenzano (VA) (Italy);13. Current address: Inventiva, 50 rue de Dijon, 21121 Daix (France);14. Current address: CISI S.C.R.L. Via G. Fantoli 16/15, 20138 Milan (Italy) |
| 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. |
| Keywords: | antitumor agents chiral resolution enantiomers Hsp90 oximes |
