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Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)\u2013based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo\u2013electron 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. 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