The nuclear receptor-binding SET domain (NSD) family of protein lysine methyltransferases consists of three members: NSD1, NSD2 and NSD3，and which predominantly catalyzes the mono-and di-methylation of histone 3 lysine 36 (H3K36). High expression, point mutations or translocations of NSD family frequently occurred in multiple types of human cancers. NSD2, also known as MMSET (multiple myeloma SET domain) or WHSC1 (Wolf-Hirschhorn syndrome candidate 1) is involved in several cellular processes, including DNA damage repair, epithelial-mesenchymal transformation (EMT) and cell cycle regulation, and was identified as an important driver in oncogenesis. Notably, NSD2 is closely related to accelerated disease progression and rapid relapse in 15-20% of multiple myeloma (MM) harboring the t (4;14) chromosomal translocation with increased levels of H3K36me2, and among the most frequently mutated genes in pediatric cancer genomes, E1099K mutant of NSD2 is hyperactivated in acute lymphoblastic leukemia. Recent studies have revealed that overexpression of NSD2 occurred in several solid tumors including bladder, prostate, glioblastoma and gastrointestinal. NSD2 is a multi-domain protein, consists of the SET domain performing the catalytic methylation function and two PWWP (proline-tryptophan-tryptophan-proline) domains. The N-terminal PWWP domain (PWWP1) acts as the reader domain that preferentially binds to the nucleosomes containing H3K36me2 while PWWP2 domain can bind to histone H3K36/79me3 and dsDNA. Though PWWP1 and PWWP2 are different in affinity to histone substrates, they have been reported to cooperate in maintaining appropriate nuclear localization. This process relies on the conserved aromatic cage consists of PWWP1 Y233, W236 and F266, which are orthogonally positioned and interact with the methylated side chain of H3K36 residue. The NSD2-PWWP1:H3K36me2 interaction plays a critical role in stabilizing NSD2 at chromatin, and then facilitates epigenetic spreading and propagation of H3K36me2which is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions for gene transcription. In carcinoma cells, H3K36me2 signal alteration underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition that is critical for metastatic. Since NSD2 is a promising target for targeted cancer therapy, several groups have reported their efforts in developing selective small-molecule inhibitors targeting the catalytic domain or the PWWP domains of NSD proteins (Figure ). Huang et al. screened a fragment library of approximately 1600 fragment-like compounds against SET domain of NSD1 with 2D-NMR experiments and found 6-chloro-1,3-benzothiazol-2-amine that binds to the SET domain. Further structure-based optimization was conducted and resulted to a covalent inhibitor BT5