Biological characterization of SN32976, a selective inhibitor of PI3K and mTOR with preferential activity to PI3Kα, in comparison to established pan PI3K inhibitors

Abstract

Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3K isoforms and mTOR, displaying preferential activity for PI3Kα and sparing of PI3Kδ 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 PI3K inhibitors with similar selectivity for PI3Kα as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3K 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 PI3Kα compared to first generation pan PI3K inhibitors, while retaining comparable anticancer activity.

Functional testing of PI3K inhibitors stratifies responders to idelalisib and identifies treatment vulnerabilities in idelalisib-refractory/intolerant chronic lymphocytic leukemia

“…The target activity of ten PI3Ki was profiled at 1 μM over a panel of up to 468 human kinases using the kinome scan assay ( Figure 1 ), and includes earlier reported data. 27;28 The inhibitors showed expected differences in their p110 isoform specificity and off-target profiles ( Figure 1 and Supplementary Table 3 ). Among the PI3Ki, compound 7n, nemiralisib and umbralisib showed p110δ isoform-specific activity with relatively few off-target activities, while copanlisib and ZSTK474 showed broad activity against all four p110 isoforms and several off-targets ( Figure 1 and Figure 2a ).…”

Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

“…Reference compounds 1 – 10 were available from earlier work, or were prepared by literature procedures…”

“…Unfortunately, compounds like 3 did not possess good bioavailability, due to limited aqueous solubility (similar to 1 itself), which led us to prepare more soluble derivatives. These included SN32976 ( 4 ), and PWT33597 ( 5 ), also known as VDC‐597, which proceeded to human clinical trial.…”