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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 |