The phosphoinositide 3-kinases are involved in a variety of cellular functions, including cell growth, proliferation, survival, and metabolism. They participate in the phosphorylation of the inositol head group of phosphatidylinositide lipids, a critical step in the activation of the PI3K pathway which plays an important role in cancer. A number of genetic abnormalities in PI3K signalling have been implicated in oncogenesis and are common to a variety of human cancers. Among these genetic lesions, gain of function mutations in the PIK3CA gene encoding the p110a catalytic subunit have been found in 30% of solid tumors. These observations have prompted interest in the development of a second generation of PI3K inhibitors which would exhibit selectivity for the alpha isoform. Such inhibitors might find therapeutic application for the treatment of PI3Ka mutant tumors while possibly avoiding undesired effects arising from the inhibition of the other isoforms. In this lecture, we describe the process that led to the identification of NVP-BYL719, a potent and selective PI3Ka inhibitor. A preliminary, preclinical evaluation of NVP-BYL719 in comparison with the pan-PI3K inhibitor, NVP-BKM120, will be presented. The biological profiles will be discussed in relation to the distinct structures of these inhibitors and their binding interactions with PI3K.

NVP-BYL719: Exploring selective inhibition of PI3Kα as a therapeutic strategy in oncology

245th National Meeting (2013)

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