Abstract 2228: Phosphatidylinositol-4-kinase - Potent and selective inhibitors of PI4Kα and PI4Kβ.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Phosphatidylinositol (PI) is a phospholipid that resides primarily on the cytosolic surface of cell membranes. PI can be phosphorylated to generate seven different phosphatidylinositol phosphates (PIPs), all of which have distinct biological activities.1 A major first step in the production of these PIPs is the conversion of PI into phosphatidylinositol-4-phosphate (PI4P) by PI4 kinase.2 Here we describe the identification of inhibitors of PI4 kinase via targeted screening of a kinase subset. This exercise has delivered inhibitors that are potent inhibitors of PI4 kinase (pIC50 >8), which are selective the α- or the β-subtypes and do not inhibit related enzymes on the PI pathway (PI3 kinase pIC50 <5 or PIP5 kinase pIC50 <4) and also exhibit good broader kinase selectivity. The effect of these useful probe compounds on cellular phosphatidylinositol-4,5-diphosphate and subsequent downstream markers will be described along with the comparison of these effects with the corresponding siRNA. 1. G. Di Paolo, P. De Camilli, Phosphoinositides in cell regulation and membrane dynamics. Nature 2006, 443, 651-657.2. T. Sasaki, S. Takasuga, J. Sasaki, S. Kofuji, S. Eguchi, M. Yamazaki, A. Suzuki, Mammalian phosphoinositide kinases and phosphatases. Progress in lipid research, 2009, 48, 307-343. Citation Format: Michael J. Waring, Darren Cross, David Andrews, Vikki Flemington, Carol Lenaghan, Jennifer McKelvie, Sarita Maman, Piotr Raubo, Graeme Robb, James Smith, Martin Swarbrick. Phosphatidylinositol-4-kinase - Potent and selective inhibitors of PI4Kα and PI4Kβ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2228. doi:10.1158/1538-7445.AM2013-2228