2. Academic Validation
  3. Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

  • bioRxiv. 2023 Feb 15:2023.02.14.528208. doi: 10.1101/2023.02.14.528208.
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,  Ryan Lumpkin 4 5,  Brittany Sandoval 2,  Cyrus Y Jin 4 5,  Scott B Ficarro 4 8,  Michelle Y Wang 4,  Shawn Xu 2,  Brian J Groendyke 4,  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,  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 6,  Eric S Fischer 4 5,  Benjamin L Ebert 2 3 10
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • 3 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • 6 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford , School of Medicine, Stanford University, Stanford, CA.
  • 7 Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX.
  • 8 Blais Proteomics Center, and Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, MA.
  • 9 Department of Pathology, Brigham and Women's Hospital, Boston, MA.
  • 10 Howard Hughes Medical Institute, Boston, MA.
PMID: 36824856 DOI: 10.1101/2023.02.14.528208
Abstract

Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular Glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of Molecular Glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 Ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. 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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