IACS-17596 is a highly potent, selective and SAM-competitive inhibitor of NSD2 (MMSET, WHSC1) with IC50 of 8.8 nM, >300-fold selective over a KMT panel including NSD1, NSD3 and SETD2.
IACS-17596 inhibits NSD2 methylation of nucleosome substrates in vitro with IC50 of 8.8 nM.
IACS-17596 also does not show activity against a panel of broad kinase selectivity.
IACS-17596 reduces the viability of a panel of KRAS mutant cell lines with IC50 values ranging from 20 to 300 nM, depletes H3K36me2 levels, also IACS-17596 inhibits colony formation in PDAC cells, high selective over non-cancerous human mesenchymal stem cells (MSCs).
IACS-17596 localizes in both the SAM-binding pocket and the catalytic channel of NSD2.
IACS-17596 induces epigenetic and epigenome-wide reprogramming in PDAC cells, suppresses oncogenic programming through H3K27me3 upregulation at H3K27me3 legacy loci.
IACS-17596  synergizes with Sotorasib to confer sustained survival with extensive tumour regression and elimination.