DNA-encoded library screening uncovers potent DNMT2 inhibitors targeting a cryptic allosteric binding site.

ABSTRACT: 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 K _D of 3.04 μM that reduces m⁵C levels in MOLM-13 tRNA and synergizes with doxorubicin to impair cell v

SUBMITTER: Frey AF 

PROVIDER: S-EPMC12396291 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature