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

  • Science. 2026 Jul 9;393(6807):188-194. doi: 10.1126/science.aef5391.
Samuel Ojeda  #  1  2 ,  Meng Wang  #  1  2 ,  Kheewoong Baek  1  2 ,  Wallace Bourgeois  3 ,  Alba Sommerschield  3 ,  Hong Yue  1  2 ,  Rebecca J Metivier  1  2 ,  Panos Karagiannis  1  2 ,  Talya S Levitz  1  2 ,  Yuan Xiong  1  2 ,  Katherine A Donovan  1  2 ,  Scott A Armstrong  3 ,  Eric S Fischer  1  2
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • # Contributed equally.
PMID: 42424456 DOI: 10.1126/science.aef5391
Abstract

Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, Estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending Cereblon (CRBN)-based Molecular Glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.

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