Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues

Related Experiment Video

Updated: Jul 12, 2026

The Development and Application of Biophysical Assays for Evaluating Ternary Complex Formation Induced by Proteolysis Targeting Chimeras (PROTACS)
07:22

The Development and Application of Biophysical Assays for Evaluating Ternary Complex Formation Induced by Proteolysis Targeting Chimeras (PROTACS)

Published on: January 12, 2024

Samuel Ojeda1,2, Meng Wang1,2, Kheewoong Baek1,2

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

Science (New York, N.Y.)
|July 9, 2026
PubMed

Insights

Researchers developed a selective molecular glue to degrade KAT2A, a protein cooperating with oncogenes. This approach shows promise for treating cancers like acute myeloid leukemia by targeting KAT2A's vulnerability.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Lysine acetyltransferases (KATs) are crucial in sustaining cancer cell programs by cooperating with oncogenes.
  • Targeting KAT proteins offers clinical efficacy, but achieving selectivity among KAT homologs is challenging.

Purpose of the Study:

  • To develop a highly selective KAT2A degrader by extending cereblon (CRBN)-based molecular glues.
  • To investigate the mechanism of CRBN-mediated KAT2A recruitment and its therapeutic potential.

Main Methods:

  • Development of novel cereblon (CRBN)-based molecular glues.
  • Cryo-electron microscopy to elucidate the CRBN-KAT2A interaction.
  • Assessment of KAT2A degradation, histone acetylation, and antiproliferative effects in cell lines and patient-derived xenografts.

Main Results:

  • Developed a molecular glue achieving exquisite selectivity for KAT2A degradation.
  • Cryo-EM revealed a novel, degron-independent recruitment mechanism involving a surface-exposed tyrosine.
  • Selective KAT2A degradation effectively reduced H3K9Ac, inhibited proliferation in AML cells, and showed in vivo efficacy.

Conclusions:

  • KAT2A is a targetable vulnerability in various malignancies.
  • Degron-independent recruitment expands the scope of CRBN-targetable proteins.
  • This strategy offers a new therapeutic avenue for cancers driven by KAT proteins.

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