IC50: 6.2 and 5.7 nM for PI3Kα and PI3Kδ, respectively
AZD8835 is a dual PI3Kα and PI3Kδ inhibitor.
The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most mutated oncogenes in human cancer. Therefore, PI3Kα is a critical target in identifying inhibitors and testing their therapeutic application.
In vitro: AZD8835 was identified as a potent dual inhibitor of PI3Kα and PI3Kδ with good selectivity versus PI3Kβ, PI3Kγ, as well as other kinases that readily inhibited cell growth with mutant PIK3CA status, such as in estrogen receptor-positive breast cancer cell lines including MCF7, BT474, and T47D [1].
In vivo: Previous animal study demonstrated that AZD8835 had antitumor efficacy in breast cancer xenograft models when AZD8835 was continuously dosed. In addition, the monotherapy of AZD8835 was found to be able to induce tumor xenograft regression by using Intermittent High-Dose Scheduling (IHDS). Furthermore, AZD8835 IHDS treatment in combination with other targeted therapeutic agents could further enhance its antitumor activity by up to 92% regression [1].
Clinical trial: A phase I, dose study has been conducted to evaluate the safety and PK of AZD8835 in patients with advanced solid tumours, and this study is still ongoing [https://clinicaltrials.gov/ct2/show/NCT02260661term=AZD8835&rank=1].
Reference:
[1] Hudson K et al. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers. Mol Cancer Ther.2016 May;15(5):877-89.