Amplification and mutations of the PIK3CA gene encoding the p110α catalytic unit of PI3Kα occur frequently in many human cancers including ca. 25% of breast cancers. The three most common mutations (E542K, E545K and H1047R) in the PIK3CA gene have been confirmed as activating mutations. The strong evidence pointing at the oncogenic nature of the PIK3CA gene mutations and their high frequency have fuelled a strong interest in developing selective inhibitors of PI3Kα.

During the lead generation phase of this project, we identified a series of 2-amino pyridines / pyrazines as potent inhibitors of PI3Kα both at the enzymatic and the cellular level. However, these initial leads displayed poor general kinase selectivity. We report the optimisation of this series, with a special focus on optimisation of general kinase selectivity. This work led to the identification of AZD8835, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ with excellent selectivity vs. PI3Kβ, PI3Kγ and an excellent general kinase selectivity. AZD8835 is a potent inhibitor of p-Akt in cells sensitive to PI3Kα inhibition (IC50 0.057 μM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50 0.049 μM in JeKo-1 B cell line), but not to cells sensitive to PI3Kβ inhibition (IC50 3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cell line) or PI3Kγ inhibition (IC50 0.53 μM in monocytic RAW264 cell line). Furthermore, AZD8835 displayed high metabolic stability and suitable physical properties for oral administration.

In vivo, inhibition of p-Akt was observed at 30 minutes and 8 hours in the PIK3CA H1047R mutant SKOV3 tumour model in mice after chronic oral administration of AZD8835 (25 mg/kg b.i.d.). AZD8835 showed excellent tumour growth inhibition in this same model after chronic oral administration (25 mg/kg b.i.d.). Based on these results, AZD8835 was selected as a clinical candidate for the treatment of PIK3CA-dependant cancers and has recently entered phase I clinical trials.

Citation Format: Bernard Barlaam, Sabina Cosulich, Benedicte Delouvrie, Martina Fitzek, Herve Germain, Stephen Green, Craig S. Harris, Kevin Hudson, Christine Lambert-van der Brempt, Maryannick Lamorlette, Le Griffon Antoine, Remy Morgentin, Gilles Ouvry, Ken Page, Georges Pasquet, Linette Ruston, Twana Saleh, Michel Vautier, Lara Ward. Discovery of AZD8835, a potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of PIK3CA-dependent cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2015-2830