Fragment-Based Screening of NSD2-PWWP1 Identifies Novel Covalent Allosteric Ligands That Diminish Methyllysine and DNA Binding Abilities of NSD2

The PWWP1 domain of NSD2 recognizes
both H3K36me2/3 and
DNA, a
function critical for its subcellular localization and oncogenic activity,
making it a promising therapeutic target. In this study, through fragment
library screening and structure–activity relationship studies,
we identified compounds that covalently bind to the C294 residue of
NSD2-PWWP1. Structural and biochemical analyses demonstrated that
compounds 13 and 16 competitively block
NSD2-PWWP1′s recognition of both H3K36me2 and DNA, thereby
impairing its nucleosome-binding ability. This study uncovers a novel
allosteric regulatory mechanism and provides a structural framework
for the development of more effective cancer therapeutics targeting
NSD2-PWWP1.