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Discovery of a novel aminopyrazine series as selective PI3Kα inhibitors. 2017
Bernard Barlaam, and
Sabina Cosulich, and
Martina Fitzek, and
Hervé Germain, and
Stephen Green, and
Lyndsey L Hanson, and
Craig S Harris, and
Urs Hancox, and
Kevin Hudson, and
Christine Lambert-van der Brempt, and
Maryannick Lamorlette, and
Françoise Magnien, and
Gilles Ouvry, and
Ken Page, and
Linette Ruston, and
Lara Ward, and
Bénédicte Delouvrié
IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.
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