The phosphatidylinositol-3-kinase (PI3K) signaling pathway plays a critical role in regulating tumor cell growth, proliferation and survival. Hotspot mutations in <i>PIK3CA</i>, 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 Gln859, leading to the discovery of primary amides as potent inhibitors of PI3K-alpha with greater than 300-fold selectivity over the other Class I PI3K isoforms. Further 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.<br/><br/>In addition, a new and direct radical-based methodology to introduce a trifluoroethylamine motif will be presented. During the attempt of replacing the primary amide within our chemical series to improve permeability, we recognized that despite the fact that amides are widely found in drugs, further applications of amide bond substitution by trifluoroethylamine surrogates are scarce, most likely due to the lack of convenient synthetic methods. Under recently developed conditions, a variety of medicinally relevant trifluoroethylaminated heteroarenes containing a wide range of functional groups were successfully synthesized.

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

256th National Meeting (2018)

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