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
  • 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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