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

Authors

Samuel Ojeda, Meng Wang, Kheewoong Baek, Wallace Bourgeois, Alba Sommerschield, Hong Yue, Rebecca J Metivier, Panos Karagiannis, Talya S Levitz, Yuan Xiong, Katherine A Donovan, Scott A Armstrong, Eric S Fischer

Published in

Science (New York, N.Y.). Volume 393. Issue 6807. Pages 188-194. Jul 09, 2026. Epub Jul 09, 2026.

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.

PMID:
42424456
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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