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