Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Sivakumaren, S. C.; Shim, H.; Zhang, T.; Ferguson, F. M.; Lundquist, M. R.; Browne, C. M.; Seo, H.-S.; Paddock, M. N.; Manz, T. D.; Jiang, B.; Hao, M.-F.; Krishnan, P.; Wang, D. G.; Yang, T. J.; Kwiatkowski, N. P.; Ficarro, S. B.; Cunningham, J. M.; Marto, J. A.; Dhe-Paganon, S.; Cantley, L. C.; Gray, N. S.

doi:10.1101/819961

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bioRxiv · 10.1101/819961

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

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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 novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4K/{beta}/{gamma}. 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 PI5P4Ks 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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Sivakumaren, S. C., Shim, H., Zhang, T., Ferguson, F. M., Lundquist, M. R., Browne, C. M., Seo, H.-S., Paddock, M. N., Manz, T. D., Jiang, B., Hao, M.-F., Krishnan, P., Wang, D. G., Yang, T. J., Kwiatkowski, N. P., Ficarro, S. B., Cunningham, J. M., Marto, J. A., Dhe-Paganon, S., Cantley, L. C., Gray, N. S.. 2019-10-25. Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors. https://doi.org/10.1101/819961

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