UNC8153 is a selective degrader of the nuclear receptor binding SET domain-containing 2 (NSD2), with a binding Kd of 24 nM. It effectively reduces NSD2 protein levels and the dimethylation of lysine 36 on histone 3 (H3K36me2) chromatin. Its simple warhead promotes proteasome-dependent degradation of NSD2 through a novel mechanism.