Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead.

Autor:	Nowak RP; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA.; Department of Cancer Biology, Dana-Farber Cancer Institute Boston MA USA., Ragosta L; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu., Huerta F; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu., Liu H; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA., Ficarro SB; Department of Cancer Biology, Department of Oncologic Pathology, and Blais Proteomics Center, and Center for Emergent Drug Targets, Dana-Farber Cancer Institute Boston MA USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston MA 02115 USA., Cruite JT; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA., Metivier RJ; Department of Cancer Biology, Dana-Farber Cancer Institute Boston MA USA., Donovan KA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA.; Department of Cancer Biology, Dana-Farber Cancer Institute Boston MA USA., Marto JA; Department of Cancer Biology, Department of Oncologic Pathology, and Blais Proteomics Center, and Center for Emergent Drug Targets, Dana-Farber Cancer Institute Boston MA USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston MA 02115 USA., Fischer ES; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA.; Department of Cancer Biology, Dana-Farber Cancer Institute Boston MA USA., Zerfas BL; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA., Jones LH; Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu nowak@crystal.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA.
Jazyk:	angličtina
Zdroj:	RSC chemical biology [RSC Chem Biol] 2023 Aug 31; Vol. 4 (11), pp. 906-912. Date of Electronic Publication: 2023 Aug 31 (Print Publication: 2023).
DOI:	10.1039/d3cb00103b
Abstrakt:	Many cereblon (CRBN) ligands have been used to develop proteolysis targeting chimeras (PROTACs), but all are reversible binders of the E3 ubiquitin ligase. We recently described the use of sulfonyl exchange chemistry to design binders that covalently engage histidine 353 in CRBN for the first time. Here we show that covalent CRBN ligands can be used to develop efficient PROTAC degraders. We demonstrate that the fluorosulfate PROTAC FS-ARV-825 covalently labels CRBN in vitro , and in cells the BRD4 degrader is insensitive to wash-out and competition by potent reversible CRBN ligands, reflecting enhanced pharmacodynamics. We anticipate that covalent CRBN-based PROTACs will enhance degradation efficiencies, thus expanding the scope of addressable targets using the heterobifunctional degrader modality. Competing Interests: LHJ serves on the SAB for, and holds equity in, Interline Therapeutics, Umbra Therapeutics, Rapafusyn Pharmaceuticals and Ananke Therapeutics. He also holds equity in Jnana Therapeutics and consults for Matchpoint Therapeutics. The Center for Protein Degradation at DFCI receives research funding from Deerfield. E. S. F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Lighthorse Therapeutics, Proximity Therapeutics, and Neomorph, Inc. (board of directors). E. S. F. is an equity holder and SAB member for Avilar Therapeutics and Photys Therapeutics and a consultant to Novartis, Sanofi, EcoR1 Capital, and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Voronoi, and Astellas. KAD is a consultant for Kronos Bio and Neomorph Inc. J. A. M. is a founder, equity holder, and advisor to Entact Bio, serves on the SAB of 908 Devices, and receives or has received sponsored research funding from Vertex, AstraZeneca, Taiho, Springworks and TUO Therapeutics. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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