Author: Jamieson, Stephen M F ; Baguley, Bruce C ; Denny, William A ; Buchanan, Christina M ; Giddens, Anna C ; Shepherd, Peter R ; Gamage, Swarna A ; Rewcastle, Gordon W ; Lee, Woo-Jeong ; Kendall, Jackie D ; Dickson, James M J

Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.

18 Jul 2017·Oncotarget

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

Article

Author: Kolekar, Sharada ; Denny, William A. ; Buchanan, Christina M. ; Lee, Woo-Jeong ; Gamage, Swarna A. ; Tsang, Kit Y. ; Smith, Greg C. ; Giddens, Anna C. ; Singh, Ripudaman ; Shepherd, Peter R. ; Rewcastle, Gordon W. ; Matthews, David J. ; Han, Weiping ; Kendall, Jackie D. ; Jamieson, Stephen M.F.

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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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	NZ	Pathway Therapeutics, Inc.	17 Jul 2017
Neoplasms	Preclinical	NZ	Auckland University	17 Jul 2017

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