The phosphatidylinositol 3 kinase (PI3K) signaling pathway plays a critical role in regulating tumor cell growth, proliferation and survival. Hotspot mutations in PIK3CA, the gene that encodes for the p110-alpha catalytic subunit of phosphatidylinositol-3-kinase, are highly prevalent in cancer and thus PI3K-alpha is a promising target for the treatment of cancer. However, exposure of PI3K inhibitors in the clinic can be limited by PI3K-isoform driven toxicities. We hypothesized that improving selectivity for PI3K-alpha relative to the other isoforms has the potential for increased tolerability in the clinical setting. Structure-based design was utilized to enhance isoform-specific interactions with Gln 859, leading to potent inhibitors of PI3K-alpha with greater than 300-fold selectivity over the other Class I PI3K isoforms. Optimization of the physico-chemical properties lead to improved permeability and decreased clearance, and overall increased bioavailability, resulting in the identification of GDC-0077 which demonstrates strong efficacy in PIK3CA mutant tumor models. In addition, GDC-0077 induces the selective degradation of the mutant p110-alpha protein in a proteasome dependent fashion. In vitro characterization and pharmacokinetic parameters modeled from preclinical species predicted low plasma clearance in human, supporting the selection of GDC-0077 as a development candidate for the treatment of patients with PIK3CA-mutant cancer. This compound is now in Phase I clinical trials.

Discovery of GDC-0077: A highly selective inhibitor of PI3K-alpha that induces degradation of mutant-p110 alpha protein

254th National Meeting (2017)

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