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

Autor: Manz TD; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123 Saarbruecken, Germany., Sivakumaren SC; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Ferguson FM; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Zhang T; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Yasgar A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850 United States., Seo HS; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Ficarro SB; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, United States.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, United States., Card JD; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, United States.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, United States., Shim H; Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, New York 10065, United States., Miduturu CV; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Simeonov A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850 United States., Shen M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850 United States., Marto JA; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, United States.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, United States., Dhe-Paganon S; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Hall MD; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850 United States., Cantley LC; Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, New York 10065, United States., Gray NS; Department of Cancer Biology, Dana-Farber Cancer Institute, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 May 14; Vol. 63 (9), pp. 4880-4895. Date of Electronic Publication: 2020 Apr 27.
DOI: 10.1021/acs.jmedchem.0c00227
Abstrakt: 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.
Databáze: MEDLINE
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