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<p>Molecular glues, small molecules that bind cooperatively at a protein-protein interface, have emerged as powerful modalities for the modulation of protein-protein interactions (PPIs) and “undruggable” targets. The systematic identification of new chemical matter with a molecular glue mechanism of action remains a significant challenge in drug discovery. Here, we present a scaffold hopping approach, using as a starting point our previously developed molecular glues for the native 14-3-3/estrogen receptor alpha (ERα) complex. The novel, computationally designed scaffold is based on the Groebke-Blackburn-Bienaymé multi-component reaction (MCR), leading to drug-like analogs with multiple points of variation, thus enabling the rapid derivatization and optimization of the scaffold. Structure-activity relationships (SAR) are developed using orthogonal biophysical assays, such as intact mass spectrometry, TR-FRET and SPR. Rational structure-guided optimization is facilitated by multiple crystal structures of ternary complexes with the glues, 14-3-3 and phospho-peptides mimicking the highly disordered C-terminus of ERα. Cellular stabilization of 14-3-3/ERα for the most potent analogs is confirmed using a NanoBRET assay with full-length proteins in live cells. Our approach highlights the potential of MCR chemistry, combined with scaffold hopping, to drive the development and optimization of unprecedented molecular glue scaffolds.</p>

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Scaffold-hopping for molecular glues targeting the 14-3-3/ERα complex

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月14日

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  • Markella Konstantinidou,
  • Marios Zingiridis,
  • Marloes A. M. Pennings,
  • Michael Fragkiadakis,
  • Johanna M. Virta,
  • Jezrael L. Revalde,
  • Emira J. Visser,
  • Christian Ottmann,
  • Luc Brunsveld,
  • Constantinos G. Neochoritis,
  • Michelle R. Arkin

摘要

Molecular glues, small molecules that bind cooperatively at a protein-protein interface, have emerged as powerful modalities for the modulation of protein-protein interactions (PPIs) and “undruggable” targets. The systematic identification of new chemical matter with a molecular glue mechanism of action remains a significant challenge in drug discovery. Here, we present a scaffold hopping approach, using as a starting point our previously developed molecular glues for the native 14-3-3/estrogen receptor alpha (ERα) complex. The novel, computationally designed scaffold is based on the Groebke-Blackburn-Bienaymé multi-component reaction (MCR), leading to drug-like analogs with multiple points of variation, thus enabling the rapid derivatization and optimization of the scaffold. Structure-activity relationships (SAR) are developed using orthogonal biophysical assays, such as intact mass spectrometry, TR-FRET and SPR. Rational structure-guided optimization is facilitated by multiple crystal structures of ternary complexes with the glues, 14-3-3 and phospho-peptides mimicking the highly disordered C-terminus of ERα. Cellular stabilization of 14-3-3/ERα for the most potent analogs is confirmed using a NanoBRET assay with full-length proteins in live cells. Our approach highlights the potential of MCR chemistry, combined with scaffold hopping, to drive the development and optimization of unprecedented molecular glue scaffolds.