Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Increased
activity of the lysine methyltransferase NSD2 driven
by translocation and activating mutations is associated with multiple
myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical
probe has been reported to date. Here, we present the first antagonists
that block the protein–protein interaction between the N-terminal
PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental
validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 μM and abrogates histone H3K36me2 binding to
the PWWP1 domain in cells. This study establishes an alternative approach
to targeting NSD2 and provides a small-molecule antagonist that can
be further optimized into a chemical probe to better understand the
cellular function of this protein.