2. Academic Validation
  3. Structure-Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Structure-Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

  • ACS Med Chem Lett. 2019 Nov 3;11(3):346-352. doi: 10.1021/acsmedchemlett.9b00402.
Theresa D Manz 1 2 3,  Sindhu C Sivakumaren 1 2,  Adam Yasgar 4,  Matthew D Hall 4,  Mindy I Davis 4,  Hyuk-Soo Seo 1 2,  Joseph D Card 5 6 7,  Scott B Ficarro 5 6 7,  Hyeseok Shim 8,  Jarrod A Marto 5 6 7,  Sirano Dhe-Paganon 1 2,  Atsuo T Sasaki 9,  Matthew B Boxer 4,  Anton Simeonov 4,  Lewis C Cantley 8,  Min Shen 4,  Tinghu Zhang 1 2,  Fleur M Ferguson 1 2,  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, 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.
  • 9 Division of Hematology and Oncology, University of Cincinnati, 3125 Eden Avenue, Cincinnati, Ohio 45267-0508, United States.
PMID: 32184968 DOI: 10.1021/acsmedchemlett.9b00402
Abstract

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important molecular players in a variety of diseases, such as Cancer. Currently available PI5P4K inhibitors are reversible small molecules, which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochemical and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our lab. Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound 30, which retained biochemical and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, compound 30 represents a highly selective pan-PI5P4K covalent lead molecule.

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