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

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. Targeted protein degradation is an exciting area of drug development for the treatment of various diseases. However, the possible protein targets have been limited mostly to those containing a particular sequence and a structural feature called the G-loop degron. Ojeda et al. identified a small molecule that degrades the lysine acetyltransferase KAT2A and does not contain the G-loop at all. Structures of KAT2A bound to the small molecule and the degrader protein cereblon revealed the interface of the distinct ternary complex. In addition to demonstrating potential for targeting proteins without a G-loop, the authors showed that the small molecule has promising preliminary activity against acute myeloid leukemia in cell lines and a mouse model. —Michael A. Funk