Abstract
The nuclear receptor binding SET domain (NSD) family of histone methyltransferases, which comprised NSD1, NSD2, and NSD3. They play a pivotal role in catalyzing mono- and dimethylation of histone H3 at lysine 36 (H3K36me1/2), a modification critical for maintaining chromatin structure and transcriptional fidelity. Dysregulation of NSD enzymes, often through overexpression, mutation, or chromosomal translocation, has been implicated in a broad spectrum of malignancies and various diseases. Due to their critical role in disease pathogenesis and recent technological advances, NSD proteins have become attractive targets for therapeutic intervention. This review highlights recent progress in developing small molecule inhibitors and chemical probes targeting NSD family members, focusing on the catalytic SET domain, the PWWP domain, and other functional motifs. Among these, several chemical classes have been investigated, including quinoline-5,8-dione, 2-aminobenzothiazole, 5-aminonaphthalene, quinazoline, purine, benzoxazinone-cyclopropylamide, and imidazole derivatives. In addition, novel strategies such as protein degradation via PROTACs and dual-target inhibitors are discussed. By systematically summarizing recent advances, this review seeks to facilitate and accelerate the development of effective NSD modulators, ultimately advancing therapeutic options for diseases driven by NSD dysregulation.