Biological characterization of SN32976, a selective inhibitor of PI3K and mTOR with preferential activity to PI3Kα, in comparison to established pan PI3K inhibitors
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Gordon W. Rewcastle1,2, Sharada Kolekar3, Christina M. Buchanan2,3, Swarna A. Gamage1, Anna C. Giddens1, Kit Y. Tsang1, Jackie D. Kendall1,2, Ripudaman Singh1, Woo-Jeong Lee3, Greg C. Smith4, Weiping Han5, David J. Matthews6, William A. Denny1,2, Peter R. Shepherd2,3 and Stephen M.F. Jamieson1,2,7
1Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
2Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
3Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
4Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, Australia
5Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
6PharmIntuition, San Francisco, CA, USA
7Department of Pharmacology and Clinical Pharmacology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
William A. Denny, email: email@example.com
Keywords: SN32976, phosphatidylinositol 3-kinase, pan PI3K inhibitor, PI3Kα-preferential, kinase selectivity
Received: January 31, 2017 Accepted: April 14, 2017 Published: May 09, 2017
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.
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