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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Dong, Aiping Benn, Caroline L. Oudhoff, Menno J. Vedadi, Masoud Gingras, Anne-claude Gerstenberger, Brian S. Kennedy, Steven Rossi, Fabio M. V. Allali-hassani, Abdellah Bunnage, Mark E. Zaph, Colby Braam, Mitchell J. S. Sudol, Marius Lambert, Jean-philippe Aman, Ahmed Fish, Paul V. Marcellus, Richard Tatlock, John H. Wu, Hong Al-awar, Rima Li, Fengling Senisterra, Guillermo A. Owen, Dafydd R. Freeman, Spencer A. Grimley, Rachel L. Brown, Peter J. Zeng, Hong Roberts, Lee Arrowsmith, Cheryl H. Barsyte-lovejoy, Dalia Kuznetsova, Ekaterina Couzens, Amber L. Schapira, Matthieu |
| Description | Author Affiliation: Barsyte-Lovejoy D ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Li F ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Oudhoff MJ ( Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T1Z3); Tatlock JH ( Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, San Diego, CA 92121); Dong A ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Zeng H ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Wu H ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Freeman SA ( Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T1Z3); Schapira M ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Senisterra GA ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Kuznetsova E ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Marcellus R ( Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); Allali-Hassani A ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Kennedy S ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Lambert JP ( Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada M5G 1X5); Couzens AL ( Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada M5G 1X5); Aman A ( Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); Gingras AC ( Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada M5G 1X5); Al-Awar R ( Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8); Fish PV ( Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom); Gerstenberger BS ( Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340); Roberts L ( Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139); Benn CL ( Neusentis Research Unit, Pfizer Worldwide Research and Development, Cambridge CB21 6GS, United Kingdom); Grimley RL ( Neusentis Research Unit, Pfizer Worldwide Research and Development, Cambridge CB21 6GS, United Kingdom); Braam MJ ( Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T1Z3); Rossi FM ( Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T1Z3); Sudol M ( Weis Center for Research, Geisinger Clinic, Danville, PA 17821); Brown PJ ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Bunnage ME ( Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139); Owen DR ( Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139); Zaph C ( Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T1Z3); Vedadi M ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); Arrowsmith CH ( Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7); |
| Abstract | SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Ki (app) = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 35 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Enzyme Inhibitors Pharmacology Epigenesis, Genetic Drug Effects Histone-Lysine N-Methyltransferase Antagonists & Inhibitors Metabolism Pyrrolidines Signal Transduction Sulfonamides Tetrahydroisoquinolines Adaptor Proteins, Signal Transducing Genetics Dose-Response Relationship, Drug Chemistry Fibroblasts MCF-7 Cells Methyltransferases Mutation Phosphoproteins Protein Structure, Tertiary Protein-Serine-Threonine Kinases Structure-Activity Relationship Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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