Nuclear receptor-binding SET domain-containing protein 1 (NSD1)

Nuclear receptor-binding SET domain-containing protein 1 (NSD1) is a histone H3 lysine 36 (H3K36) methyltransferase that primarily catalyzes mono- and di-methylation, playing a pivotal role in chromatin regulation and gene expression [2, 10]. It acts as a bifunctional transcriptional coregulator, interacting with various nuclear receptors to either activate or repress target genes depending on the cellular context [8, 13]. Germline loss-of-function mutations in NSD1 are the hallmark of Sotos syndrome, a childhood overgrowth disorder, highlighting its essential role in normal human development [4, 5, 8]. In oncology, NSD1 is frequently altered; for instance, the NUP98-NSD1 fusion protein drives aggressive forms of acute myeloid leukemia, while inactivating mutations are common in head and neck squamous cell carcinomas [3, 8, 14]. Therapeutic targeting of NSD1 is an active area of research, with the development of first-in-class covalent inhibitors like BT5 that specifically target the catalytic SET domain to disrupt oncogenic signaling [14]. However, drug development faces challenges such as the potential for developmental toxicity and the need for high selectivity among the closely related NSD family members [12, 16].

Other names

KMT3BARA267SOTOSSOTOS1STOHistone-lysine N-methyltransferase H3 lysine-36 specificNR-binding SET domain-containing protein

Covalent inhibition of the SET domain to block H3K36 dimethylation and downstream oncogenic gene expression.