Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors.

Cell Chemical Biology
SIndhu Carmen SivakumarenNathanael S Gray

Abstract

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

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Citations

May 19, 2021·Proceedings of the National Academy of Sciences of the United States of America·Song ChenYa Ha
Jun 19, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Oksana GoroshchukCaroline Palm-Apergi

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