Lysine acetyltransferases (KATs) frequently cooperate with oncogenes such as c-Myc, estrogen receptor, and KMT2A-fusions to sustain malignant programs. Therapeutic targeting of KAT proteins has shown clinical efficacy, yet achieving homolog-selectivity for most KATs remains a major challenge. Here, by extending CRBN-based molecular glues beyond the canonical degron space, we develop a degrader of KAT2A exhibiting biochemical selectivity over all members of the KAT family. Cryo-EM structures reveal that CRBN engages KAT2A independent of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Optimized molecular glues demonstrate that selective KAT2A degradation leads to potent ablation of H3K9Ac, antiproliferative effects in AML cell lines, and in vivo efficacy in a patient-derived xenograft model. Overall, these findings establish KAT2A as a targetable vulnerability, laying the foundation for the development of KAT2A-degrading molecular glues to treat a wide range of malignancies. More generally, the unanticipated binding mode suggests that CRBN-based molecular glues may be limited only by the accessible chemical diversity.