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.
Highlights
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates a number of crucial cellular processes, including growth, survival, angiogenesis, migration and metabolism [1, 2, 3, 4]
The biochemical potency of SN32976 against the major class I PI3K isoforms and mammalian target of rapamycin (mTOR) was determined against purified recombinant protein and compared to five PI3K/mTOR inhibitors that have been clinically evaluated: ZSTK474, dactolisib, pictilisib, buparlisib and omipalisib (Table 1)
SN32976 is a potent inhibitor of class I PI3K enzymes and mTOR with similar activity to PI3Kα, β, γ and mTOR to that of ZSTK474, dactolisib, pictilisib and buparlisib, but less potency than omipalisib
Summary
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates a number of crucial cellular processes, including growth, survival, angiogenesis, migration and metabolism [1, 2, 3, 4]. PI3K signaling is frequently dysregulated in cancer resulting in persistent pathway activation [5, 6]. Genetic or epigenetic inactivation of the negative regulator of PI3K activity, the tumor suppressor PTEN, is found in a number of cancers [9]. Several other genes downstream of PI3K are frequently mutated, such as AKT genes, MTOR, TSC1 and TSC2 [7]. In addition to activating mutations, amplification of genes encoding PI3K/AKT enzymes or receptor tyrosine kinases (e.g. EGFR, HER2, KIT, PDGFRα, MET) can promote PI3K signaling [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
