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<p>Molecular glue degraders for therapeutic target proteins are emerging as a strategy in drug discovery. Here, we modify a&#xa0;BRD9 ligand with specific chemical fragments to create degrader compounds that we call Targeted Glues. When bound to the target protein, these create an altered protein-ligand interface that is recognised by a ligase. This interaction between the target and the E3 ligase leads to protein degradation and is stabilised by a reversible covalent interaction between our molecule and a specific cysteine in the ligase. By screening a library of BRD9 targeted compounds we discover <b>AMPTX1</b>, a potent selective and reversibly covalent BRD9 degrader. In cells, <b>AMPTX-1</b> selectively recruits the E3 ligase, DCAF16, to BRD9 and drives BRD9 degradation, as demonstrated by co-immunoprecipitation-mass spectrometry. BRD9 degradation is primarily dependent on the engagement of the surface Cys58 of DCAF16; the formation of a covalent adduct to DCAF16 is facilitated by ternary complex formation with BRD9. BRD9 degradation is also achieved in vivo with <b>AMPTX-1</b> in a mouse xenograft model after oral dosing due to the drug-like, orally bioavailable properties of the compound. This supports the concept that covalent recruitment of DCAF16 is a viable approach in the development of therapeutic degraders.</p>

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Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Scott J. Hughes,
  • Wojciech J. Stec,
  • Colin T. R. Davies,
  • David McGarry,
  • Alicia Williams,
  • Marta Carrara,
  • Ivan Del Barco Barrantes,
  • Rebecca Harris,
  • Anna Tasegian,
  • Dominic D. G. Owens,
  • Alexander Fawcett,
  • John Hellicar,
  • Aleksandra Azevedo,
  • Gregor P. Meier,
  • Andrew C. Runcie,
  • Liliana Greger,
  • Martin O’Rourke,
  • Ian Churcher,
  • Martin Pass,
  • Giles A. Brown,
  • Alessio Ciulli,
  • Louise K. Modis,
  • Andrea Testa

摘要

Molecular glue degraders for therapeutic target proteins are emerging as a strategy in drug discovery. Here, we modify a BRD9 ligand with specific chemical fragments to create degrader compounds that we call Targeted Glues. When bound to the target protein, these create an altered protein-ligand interface that is recognised by a ligase. This interaction between the target and the E3 ligase leads to protein degradation and is stabilised by a reversible covalent interaction between our molecule and a specific cysteine in the ligase. By screening a library of BRD9 targeted compounds we discover AMPTX1, a potent selective and reversibly covalent BRD9 degrader. In cells, AMPTX-1 selectively recruits the E3 ligase, DCAF16, to BRD9 and drives BRD9 degradation, as demonstrated by co-immunoprecipitation-mass spectrometry. BRD9 degradation is primarily dependent on the engagement of the surface Cys58 of DCAF16; the formation of a covalent adduct to DCAF16 is facilitated by ternary complex formation with BRD9. BRD9 degradation is also achieved in vivo with AMPTX-1 in a mouse xenograft model after oral dosing due to the drug-like, orally bioavailable properties of the compound. This supports the concept that covalent recruitment of DCAF16 is a viable approach in the development of therapeutic degraders.