Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors PMID: 32130941

ADC Targets in Oncology

2026-04-10

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].

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.