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Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation

Yixiang Jiang1, Guochao Chen2,3, Xiao-Meng Li1

  • 1Departments of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

Journal of the American Chemical Society
|December 11, 2020
PubMed

Insights

Researchers developed a novel cyclopeptide inhibitor, JYX-3, that selectively targets the AF9 YEATS domain. This breakthrough offers a promising new avenue for developing drugs against YEATS domain-related diseases like cancer.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Drug Discovery

Background:

  • YEATS domains are epigenetic readers of histone lysine acetylation (Kac) and crotonylation (Kcr).
  • Dysfunctional YEATS-Kac/Kcr interactions are implicated in human diseases, including cancer.
  • YEATS domains represent promising therapeutic targets.

Purpose of the Study:

  • To develop selective inhibitors for YEATS domains, specifically differentiating between AF9 and ENL YEATS domains.
  • To identify novel binding sites for achieving selectivity.
  • To validate the efficacy of selective inhibitors in cellular contexts.

Main Methods:

  • Identification of a proximal allosteric site distinct from the acyllysine-binding pocket.
  • Design and synthesis of conformationally preorganized cyclopeptides.
  • Biochemical assays to determine binding affinity and selectivity.
  • Cell-based assays to assess target engagement and functional effects.

Main Results:

  • A novel proximal site differentiating AF9 YEATS from ENL YEATS was identified.
  • Combinatorial targeting of the acyllysine pocket and the proximal site yielded selective AF9 YEATS inhibitors.
  • The cyclopeptide JYX-3 demonstrated a 38-fold higher binding affinity for AF9 YEATS over ENL YEATS.
  • JYX-3 engaged AF9 in cells, disrupted its chromatin recruitment, and suppressed target gene transcription.

Conclusions:

  • Selective inhibition of YEATS domains, particularly AF9, is achievable through targeting both the acyllysine pocket and an adjacent allosteric site.
  • JYX-3 represents a potent and selective inhibitor of AF9 YEATS.
  • This study provides a foundation for developing novel therapeutics for YEATS domain-associated pathologies.

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