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

Authors :
Sirano Dhe-Paganon
Theresa D. Manz
Lewis C. Cantley
Scott B. Ficarro
Hyuk-Soo Seo
Marcia N. Paddock
Mingfeng Hao
Nathanael S. Gray
Tinghu Zhang
Baishan Jiang
Hyeseok Shim
Jarrod A. Marto
Nicholas Kwiatkowski
Diana G. Wang
Christopher M. Browne
James M. Cunningham
T. Jonathan Yang
Sindhu Carmen Sivakumaren
Mark R. Lundquist
Fleur M. Ferguson
Pranav Krishnan
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SummaryThe 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 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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....0bc1b0cef434a17aa0f69572842f5ff5
Full Text :
https://doi.org/10.1101/819961