Discovery and Development of SPR519 as a Potent, Selective, and Orally Bioavailable Inhibitor of PI3Kα and mTOR Kinases for the Treatment of Solid Tumors

Herein, we report
the identification and preclinical profile of
a lead compound 10, (SPR519) as an equally
potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC50 of low sub-micromolar range among various
tested cancer cell lines such as A2780 (0.23 μM), PC3 (0.48
μM), and SKOV3 (0.50 μM). When administrated orally, it
shows a considerably high plasma exposure (area under curve: 26,858
nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals
with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified
lead compound demonstrates significant efficacy and bioavailability
in ovarian and colon cancer xenograft models when evaluated for dose-ranging
efficacy studies, at a dose as low as 2.5 mg/kg.