Phosphoinositide 3-kinase (PI3K) is an important member of the PI3K/Akt/mTOR signaling pathway, playing a role in cell growth, proliferation, and survival. PIK3CA, the gene that encodes the catalytic subunit of PI3K-alpha protein, is a commonly mutated oncogene. It is implicated in a wide range of cancers, particularly in breast cancer. Herein we report a scaffold hopping approach that led to the discovery of a novel, highly potent chemical series. These compounds demonstrate highly selective inhibition of PI3K-alpha over the other Class I PI3K isoforms as well as the broader kinome. This series presented challenges such as poor solubility and permeability, and low oral bioavailability. The structure activity relationships indicated specific areas of polarity and the presence of hydrogen bond donors were essential for maintaining activity. These challenges were addressed through the use of structure based design, modulation of physicochemical properties, and in-silico ADME property modelling. Optimized inhibitors with good oral bioavailability show strong efficacy in PIK3CA tumor xenograft models. Overall, the high potency and selectivity make this series of great interest, as selective inhibitors have the potential to allow for treatment of PI3K-alpha-driven cancers with a greater therapeutic index.

Discovery of novel class of alpha selective PI3K inhibitors

254th National Meeting (2017)

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