1. Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors.
- Author
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Sivakumaren, Sindhu Carmen, Shim, Hyeseok, Zhang, Tinghu, Ferguson, Fleur M., Lundquist, Mark R., Browne, Christopher M., Seo, Hyuk-Soo, Paddock, Marcia N., Manz, Theresa D., Jiang, Baishan, Hao, Ming-Feng, Krishnan, Pranav, Wang, Diana G., Yang, T. Jonathan, Kwiatkowski, Nicholas P., Ficarro, Scott B., Cunningham, James M., Marto, Jarrod A., Dhe-Paganon, Sirano, and Cantley, Lewis C.
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CANCER cell proliferation , *DELETION mutation , *SMALL molecules , *LIPIDS , *CELL lines - 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. • Inhibitor THZ-P1-2 shows PI5P4K enzyme inhibition and target engagement in cells • THZ-P1-2 covalently targets unannotated cysteines outside the PI5P4K active site • AML/ALL cell lines are broadly sensitive to THZ-P1-2's covalent effects • PI5P4K inhibition causes autophagy disruption and upregulates TFEB signaling PI5P4K, an understudied kinase family, is essential in various disease contexts. Sivakumaren et al. develop and characterize PI5P4K inhibitor THZ-P1-2, which targets unique cysteines, exhibits effects in biochemical and cellular assays, displays anticancer activity in leukemia cell lines, and causes defects in autophagy similar to PI5P4K gene knockdown or deletion. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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