2. Academic Validation
  3. Template-assisted covalent modification underlies activity of covalent molecular glues

Template-assisted covalent modification underlies activity of covalent molecular glues

  • Nat Chem Biol. 2024 Jul 29. doi: 10.1038/s41589-024-01668-4.
Yen-Der Li # 1 2 3,  Michelle W Ma # 1 4 5,  Muhammad Murtaza Hassan # 6,  Moritz Hunkeler 4 5,  Mingxing Teng 7,  Kedar Puvar 4 5,  Justine C Rutter 2 3,  Ryan J Lumpkin 4 5,  Brittany Sandoval 2,  Cyrus Y Jin 4 5,  Anna M Schmoker 4 5,  Scott B Ficarro 4 8 9,  Hakyung Cheong 4,  Rebecca J Metivier 4,  Michelle Y Wang 4,  Shawn Xu 2,  Woong Sub Byun 6,  Brian J Groendyke 4,  Inchul You 6,  Logan H Sigua 4,  Isidoro Tavares 4 8,  Charles Zou 2,  Jonathan M Tsai 2 3 9,  Paul M C Park 2 3,  Hojong Yoon 2 3,  Felix C Majewski 6,  Haniya T Sperling 2 3,  Jarrod A Marto 4 8 9,  Jun Qi 4,  Radosław P Nowak 4 5,  Katherine A Donovan 4 5,  Mikołaj Słabicki 2 3,  Nathanael S Gray 10,  Eric S Fischer 11 12,  Benjamin L Ebert 13 14 15
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 7 Center for Drug Discovery, Department of Pathology & Immunology, and Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
  • 8 Blais Proteomics Center and Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 9 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • 10 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA. nsgray01@stanford.edu.
  • 11 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. eric_fischer@dfci.harvard.edu.
  • 12 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. eric_fischer@dfci.harvard.edu.
  • 13 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. benjamin_ebert@dfci.harvard.edu.
  • 14 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. benjamin_ebert@dfci.harvard.edu.
  • 15 Howard Hughes Medical Institute, Boston, MA, USA. benjamin_ebert@dfci.harvard.edu.
  • # Contributed equally.
PMID: 39075252 DOI: 10.1038/s41589-024-01668-4
Abstract

Molecular Glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing Molecular Glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 Ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes the formation of BRD4-degrader-DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK-BRD4BD2 interaction through trans-labeling of GAK. Together, our work establishes 'template-assisted covalent modification' as a mechanism for covalent Molecular Glues, which opens a new path to proximity-driven pharmacology.

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