DNA-encoded library screening uncovers potent DNMT2 inhibitors targeting a cryptic allosteric binding site
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DNMT2 (TRDMT1) is a human RNA methyltransferase implicated in various disease processes. However, small-molecule targeting of DNMT2 remains challenging due to poor selectivity and low cellular availability of known S-adenosylhomocysteine (SAH)-derived ligands. In this study, a DNA-encoded library (DEL) screen identified five non-SAH-like chemotypes that selectively bind DNMT2, including three peptidomimetics. Orthogonal assays confirmed target engagement, and X-ray crystallography revealed a previously unknown allosteric binding pocket formed via active site loop rearrangement. Guided by structural insights, the authors optimized a lead compound with a KD of 3.04 μM that reduces m5C levels in MOLM-13 tRNA and synergizes with doxorubicin to impair cell viability. These inhibitors exhibit unprecedented selectivity over other methyltransferases, offering a promising scaffold for future DNMT2-targeting therapeutics. Beyond pharmacological implications, the study provides conceptual advances in understanding allosteric modulation and structural plasticity of DNMT2.
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iScience, 28, 9, Elsevier, Amsterdam ; Boston ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis, 2025, https://doi.org/10.1016/j.isci.2025.113300