Abstact

The PIP4K family of lipid kinases phosphorylates the rare phospholipid PI(5)P at the 4-position, generating PI(4,5)P(2) inside the cell. Although the functions of PIP4K, as well as the intracellular pools of PI(5)P and PI(4,5)P(2), remain incompletely understood, there are emerging interests in developing inhibitors to target these kinases since their genetic ablations have broad tumor-suppressive and other beneficial effects. Here, we report continued optimization of a previously discovered 2-amino-dihydropteridinone PIP4K2A/2B inhibitor and demonstrate, for the first time that pharmacological inhibition of PIP4K2A/2B suppresses solid tumor growth in vivo. The tumor-suppressive effect of the inhibitor appears to be non-tumor cell-autonomous and is likely mediated by components of the tumor microenvironment, including macrophages that commonly adopt alternatively activated states and support tumor growth. Our findings suggest a potential role for PIP4K activity in tumor-associated macrophages and provide a rationale for further exploring pharmacological targeting of these lipid kinases in cancer.