2. Academic Validation
  3. Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-136351
    99.86%, PI5P4K Inhibitor