NSD2 (nuclear receptor-binding SET domain-containing 2) is a protein lysine methyltransferase. It belongs to the NSD family, which also includes NSD1 and NSD3, and that predominantly mono- and dimethylates lysine 36 of histone 3 (H3K36). NSD2 is an oncoprotein that is aberrantly expressed, amplified, or somatically mutated in multiple types of cancer. The t(4;14) NSD2 translocation in multiple myeloma and the hyperactivating NSD2 mutation E1099K in a subset of pediatric acute lymphoblastic leukemia result in altered chromatin methylation that drives oncogenesis. NSD2 is an attractive therapeutic target, efforts to target the catalytic SET domain with small-molecule inhibitors have so far met with little success. NSD2 has multiple protein-protein interaction domains that may be clinically relevant, including plant homeodomain and PWWP (proline-tryptophan-tryptophan-proline) domains. In this study, MR837 is an inhibitor of NSD2-PWWP1. MR837 can bind with human nuclear receptor binding SET domain protein 2.

MR837 blocks the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. It also binds to the NSD2-PWWP1 domain. PWWP domains represent a chemically tractable target class. In addition, PWWP ligands could also serve as chemical handles toward the development of PROTACs that catalyze the proteasomal degradation of PWWP-containing proteins. Furthermore, the domains are often in multi-modular proteins. They involve in transcriptional regulation or DNA repair. The pharmacological targeting of PWWP domains could provide an avenue to deregulate the function of these proteins.

In summary, this study establishes an alternative approach to targeting NSD2. MR837 is a potent NSD2-PWWP1 protein-protein interaction inhibitor. Moreover, it is a useful tool for better understand the cellular function of this protein.


Ferreira de Freitas R,  et al. J Med Chem. 2021;64(3):1584-1592.