This is the first of a two-part account on the chemical discovery and development of Ph I clinical candidate, GDC-0032 . During the course of identifying isoform-selective PI3K inhibitors, we advanced our HTS-derived benzoxepin scaffold into inhibitors that were potent, selective and had sufficient in vivo activity to elicit tumor growth inhibition in mouse xenograft. Due to low unbound drug exposure, we found that the inhibitors had limited efficacy. Our optimization efforts focused on improving this parameter by addressing the physical properties of compounds. This eventually led to the discovery of GDC-0032 , which had high unbound drug exposure and robust in vivo anti-tumor activity allowing for progression as a clinical candidate for the treatment of solid tumors.

Part I: Discovery of �-sparing PI3K inhibitor GDC-0032 by optimization of unbound drug exposure

248th National Meeting (2014)

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