Biological characterization of SN32976, a selective inhibitor of PI3κ and mTOR with preferential activity to PI3κα, in comparison to established pan PI3κ inhibitors

Abstract

Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3κ) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3κ inhibitors, which target class Ia PI3κ isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3κ inhibitor, for its biochemical potency against PI3κ isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3κ inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3κ isoforms and mTOR, displaying preferential activity for PI3κa and sparing of PI3κd relative to the other inhibitors, while showing less off-target activity than the clinical inhibitors in a panel of 442 kinases. The major metabolites of SN32976 were also potent PI3κ inhibitors with similar selectivity for PI3κa as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3κ inhibitors in cellular assays, inhibiting pAKT expression and cell proliferation at nM concentrations, and in animal models, inducing a greater extent and duration of pAKT inhibition in tumors than pictilisib, dactolisib and omipalisib at similarly tolerated dose levels and inhibiting tumor growth to a greater extent than dactolisib and ZSTK474 and with similar efficacy to pictilisib and omipalisib. These results suggest that SN32976 is a promising clinical candidate for cancer therapy with enhanced kinase selectivity and preferential inhibition of PI3κα compared to first generation pan PI3κ inhibitors, while retaining comparable anticancer activity.