Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

  • Cell Chem Biol. 2020 May 21;27(5):525-537.e6. doi: 10.1016/j.chembiol.2020.02.003.
Sindhu Carmen Sivakumaren  1 ,  Hyeseok Shim  2 ,  Tinghu Zhang  1 ,  Fleur M Ferguson  1 ,  Mark R Lundquist  2 ,  Christopher M Browne  1 ,  Hyuk-Soo Seo  1 ,  Marcia N Paddock  2 ,  Theresa D Manz  3 ,  Baishan Jiang  1 ,  Ming-Feng Hao  1 ,  Pranav Krishnan  4 ,  Diana G Wang  2 ,  T Jonathan Yang  2 ,  Nicholas P Kwiatkowski  5 ,  Scott B Ficarro  6 ,  James M Cunningham  4 ,  Jarrod A Marto  7 ,  Sirano Dhe-Paganon  1 ,  Lewis C Cantley  8 ,  Nathanael S Gray  9
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2. Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbruecken, Germany.
  • 4. Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8. Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA. Electronic address: [email protected].
  • 9. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 32130941 DOI: 10.1016/j.chembiol.2020.02.003
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.

Keywords
PI5P4K; autophagy; cancer; covalent inhibitor; drug discovery; kinase; phosphoinositide.
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