Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation†,10.1039/C3CC48391F

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Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation†

Michael J. Waring,David M. Andrews,Paul F. Faulder,Vikki Flemington,Jennifer C. McKelvie,Sarita Maman,Marian Preston,Piotr Raubo,Graeme R. Robb,Karen Roberts,Rachel Rowlinson,James M. Smith,Martin E. Swarbrick,Iris Treinies,Jon J. G. Winter,Robert J. Wood

Chemical Communications Pub Date : 12/13/2013 00:00:00 , DOI:10.1039/C3CC48391F

Abstract

Two series of inhibitors of type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently and selectively inhibit the α- and the β-isoforms with no significant activity towards related kinases in the pathway. In a cellular environment, inhibition of the α- but not the β-subtype led to a reduction in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate concentration, causing inhibition of inositol-1-phosphate formation and inhibition of proliferation in a panel of cancer cell lines.