Discovery of a Potent and Isoform-Selective Targeted Covalent Inhibitor of the Lipid Kinase PI3Kα

PI3K alpha has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3K alpha. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3K alpha on cysteine 862 (C862), an amino acid unique to the a isoform, and that PI3K beta, -gamma, and -delta are not covalently modified. 3 is able to potently (EC50 < 100 nM) and specifically inhibit signaling in PI3K alpha-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3K alpha, was used to investigate the duration of occupancy of 3 with PI3K alpha in vivo. This is the first report of a PI3K alpha-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3K alpha.