Recent advances in nuclear receptor-binding SET domain 2 (NSD2) inhibitors: An update and perspectives.

Nuclear receptor-binding SET domain 2 (NSD2) is a histone lysine methyltransferase (HKMTase), which is mainly responsible for the di-methylation of lysine residues on histones, which are involved in the regulation of various biological pathways. The amplification, mutation, translocation, or overexpression of NSD2 can be linked to various diseases. NSD2 has been identified as a promising drug target for cancer therapy. However, relatively few inhibitors have been discovered and this field still needs further exploration. This review provides a detailed summary of the biological studies related to NSD2 and the current progress of inhibitors, research, and describes the challenges in the development of NSD2 inhibitors, including SET (su(var), enhancer-of-zeste, trithorax) domain inhibitors and PWWP1 (proline-tryptophan-tryptophan-proline 1) domain inhibitors. Through analysis and discussion of the NSD2-related crystal complexes and the biological evaluation of related small molecules, we hope to provide insights for future drug design and optimization methods that will stimulate the development of novel NSD2 inhibitors.