The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in driving cell growth, migration and survival in many tumor types.  Given the prevalent occurrence of mutation or activation of this pathway in cancer patients, the PI3Ks have become popular targets for small molecule inhibition.  Starting from a lipophilic 2-amido-thienobenzopyran HTS hit, this presentation will detail major structure and property based changes that improved potency, selectivity and pharmacokinetic properties leading to clinical PI3K inhibitor GDC-0032.  In addition, a novel hypothesis for the PI3K� sparing activity of GDC-0032 and similar inhibitors will be disclosed.

Major structure-based discoveries en route to clinical PI3K-inhibitor GDC-0032

246th National Meeting (2013)

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