2. Academic Validation
  3. Discovery and Structure-Activity Relationship Study of ( Z)-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Discovery and Structure-Activity Relationship Study of ( Z)-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

  • J Med Chem. 2020 May 14;63(9):4880-4895. doi: 10.1021/acs.jmedchem.0c00227.
Theresa D Manz 1 2 3,  Sindhu Carmen Sivakumaren 1 2,  Fleur M Ferguson 1 2,  Tinghu Zhang 1 2,  Adam Yasgar 4,  Hyuk-Soo Seo 1 2,  Scott B Ficarro 5 6 7,  Joseph D Card 5 6 7,  Hyeseok Shim 8,  Chandrasekhar V Miduturu 1 2,  Anton Simeonov 4,  Min Shen 4,  Jarrod A Marto 5 6 7,  Sirano Dhe-Paganon 1 2,  Matthew D Hall 4,  Lewis C Cantley 8,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 3 Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123 Saarbruecken, Germany.
  • 4 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850 United States.
  • 5 Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, United States.
  • 6 Department of Oncologic Pathology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
  • 7 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 8 Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, New York 10065, United States.
PMID: 32298120 DOI: 10.1021/acs.jmedchem.0c00227
Abstract

Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for Cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted in compounds with low- to sub-micromolar potencies. Here, we report the identification of CVM-05-002 using a high-throughput screen of PI5P4Kα against our in-house kinase inhibitor library. CVM-05-002 is a potent and selective inhibitor of PI5P4Ks, and a 1.7 Å X-ray structure reveals its binding interactions in the ATP-binding pocket. Further investigation of the structure-activity relationship led to the development of compound 13, replacing the rhodanine-like moiety present in CVM-05-002 with an indole, a potent pan-PI5P4K inhibitor with excellent kinome-wide selectivity. Finally, we employed isothermal cellular thermal shift assays (CETSAs) to demonstrate the effective cellular target engagement of PI5P4Kα and -β by the inhibitors in HEK 293T cells.

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