Identification of Inhibitors of the Lipid Kinase PI5P4Ka/B as Potential Anti-Cancer Agents

National Center For Advancing Translational Sciences

Investigators

Abstract

This collaborative team - composed of groups from Weill Cornell Medical College, Harvard Medical School and the Dana Farber Cancer Institute and NCATS - aims to build on previous research by uncovering novel inhibitors of the lipid kinase PI5P4Ka/ as potential anti-cancer agents indications. During this period, the team continued hit-to-lead evaluation efforts stemming from previously completed high-throughput screening efforts. Several rounds of structure activity studies were performed to improve potency and efficacy of hits of interest, as well as to address physiochemical liabilities. Key analogs have been characterized in vitro models in binding assays and in an orthogonal functional biochemical assay that measured substrate phosphorylation. A lead analog has been co-crystallized in PI5P4Kb and PK has been obtained for two lead compounds. Cell based characterization is ongoing. Recent work has shown that the compounds are able to kill cancer cells when autophagy is activated.