Amplification and mutations of the PIK3CA gene encoding the p110α catalytic unit of PI3Ka occur frequently in many human cancers, including ca. 25% of breast cancers. In addition, three common mutations in the PIK3CA gene have been confirmed as activating mutations. Similarly, several studies have highlighted the dependency of PTEN deficient tumours to PI3Kβ activity. Finally specific inhibition of PI3Kδ has demonstrated clinical efficacy against human B-cell cancers. All these results have fuelled a renewed interest in the area of PI3K isoform selective inhibitors. We will describe the different strategies we have used to identify potent and selective PI3Kα and PI3Kβ inhibitors with suitable properties for oral administration. Starting from a potent PI3Kα inhibitor having poor general kinase selectivity, we will describe our efforts leading to the identification of AZD8835, with a focus on improving kinase selectivity using structural information for identifying key exploitable differences between PI3Kα and other kinases. Additionally, starting from TGX-221, a PI3Kβ selective inhibitor having poor physicochemical properties, we will describe the medicinal chemistry strategies we employed, specifically focussing on optimisation of physicochemical and DMPK properties while conserving high PI3Kβ selectivity. This work led to the identification of AZD8186. AZD8835 is a potent PI3Kα/δ inhibitor and displays good kinase selectivity, in particular within the PIKK superfamily. AZD8835 shows inhibition of phosphorylation of Akt in cells sensitive to PI3Kα inhibition (IC50 0.090 μM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50 0.049 µM in Jeko B cell line). In vivo, AZD8835 demonstrated strong pharmacodynamic modulation of p-Akt and gave excellent tumour growth inhibition in PIK3CA H1047R mutant SKOV3 tumour bearing mice after oral administration. AZD8186 is a potent PI3Kβ/δ inhibitor and displays good kinase selectivity, in particular within the PIKK superfamily. AZD8186 shows inhibition of phosphorylation of Akt in cells sensitive to PI3Kβ inhibition (IC50 0.003 μM in PTEN null breast adenocarcinoma MDA-MB-468 cells) and in cells sensitive to PI3Kδ inhibition (IC50 0.017 μM in Jeko B cell line). In vivo, AZD8186 showed profound pharmacodynamic modulation of p-Akt and showed complete inhibition of tumour growth in PTEN-null PC3 prostate tumour bearing mice after oral administration.

Discovery of two clinical candidates as isoform selective PI3K inhibitors: AZD8835 a potent and selective inhibitor of PI3Kα/δ and AZD8186 a potent and selective inhibitor of PI3Kβ/δ for the treatment of cancers

255th National Meeting (2018)

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