Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

Nuclear receptor binding SET domain proteins (NSDs) catalyzethemono- or dimethylation of histone 3 lysine 36 (H3K36me1 and H3K36me2),using S-adenosyl-l-methionine (SAM) as amethyl donor. As a key member of the NSD family of proteins, NSD2plays an important role in the pathogenesis and progression of variousdiseases such as cancers, inflammations, and infectious diseases,serving as a promising drug target. Developing potent and specificNSD2 inhibitors may provide potential novel therapeutics. SeveralNSD2 inhibitors and degraders have been discovered while remainingin the early stage of drug development. Excitingly, KTX-1001, a selectiveNSD2 inhibitor, has entered clinical trials. In this Perspective,the structures and functions of NSD2, its roles in various human diseases,and the recent advances in drug discovery strategies targeting NSD2have been summarized. The challenges, opportunities, and future directionsfor developing NSD2 inhibitors and degraders are also discussed.