| Autor: |
Rewcastle GW; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand., Kolekar S; Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Buchanan CM; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.; Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Gamage SA; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Giddens AC; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Tsang KY; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Kendall JD; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand., Singh R; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Lee WJ; Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Smith GC; Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, Australia., Han W; Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Matthews DJ; PharmIntuition, San Francisco, CA, USA., Denny WA; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand., Shepherd PR; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.; Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand., Jamieson SMF; Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.; Department of Pharmacology and Clinical Pharmacology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. |
| Abstrakt: |
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. |
