Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.
This study explores a new method for selectively targeting KAT2A in cancer, but specific results are not detailed in the abstract.
Where it sits
this study against the rest of the argireline corpusSummary and findings
This study investigates the recruitment of KAT2A by CRBN molecular glues, focusing on its potential to degrade KAT2A selectively. The research includes in vitro effects on acute myeloid leukemia cell lines and in vivo outcomes in a patient-derived xenograft model. No specific numeric outcomes are provided in the abstract.
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.
Background
Not reported in abstract.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Limitations
Not reported in abstract.