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The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C 4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC 50 = 20/376/204/46 nM) and mTOR (IC 50 = 189 nM), potent functional suppression of AKT phosphorylation (IC 50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C 4 sulfone chain and a fluorine on the C 6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines