Literature reports have shown that PI3K signaling in PTEN mutated / null tumors may be dependent on the PI3Kβ isoform for pathway signaling. This isoform dependence provides a hypothesis for the investigation of PI3Kb selective inhibitors as potential treatment for patients with PTEN mutated tumors. Screening of a PI3K biased library revealed single hit with PI3Kb selectivity over the PI3Ka isoform. Compound optimization led to selective inhibitors of PI3Kb kinase with good cell activity, no off-target promiscuity, physiochemical, and ADME properties. Example compounds demonstrated a pharmacodynamic response and antitumor activity in PTEN deficient xenografts.<br/>

Discovery of substituted morpholinothiophene and morpholinothiazole carboxylic acids as selective inhibitors of PI3Kb kinase

249th National Meeting (2015)

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