Discovery of a novel aminopyrazine series as selective PI3Kα inhibitors. Issue 13 (1st July 2017)

• Record Type: Journal Article
• Authors: Barlaam, Bernard; Cosulich, Sabina; Fitzek, Martina; Germain, Hervé; Green, Stephen; Hanson, Lyndsey L.; Harris, Craig S.; Hancox, Urs; Hudson, Kevin; Lambert-van der Brempt, Christine; Lamorlette, Maryannick; Magnien, Françoise; Ouvry, Gilles; Page, Ken; Ruston, Linette; Ward, Lara; Delouvrié, Bénédicte
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 13(2017)
• Page Start: 3030
• Page End: 3035
• Publication Date: 2017-07-01
• Subjects: PI3Kα inhibitor -- Rational design -- Kinase selectivity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.05.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 compound5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50 mg/kg twice daily orally) in the MCF7 xenograft model in mice.