LLC0424 is a potent and selective cereblon-based PROTAC nuclear receptor-binding SET domain-containing 2 (NSD2) degrader. LLC0424 effectively degraded NSD2 with a DC50 of 20 nM in RPMI-8402 cells. LLC0424 selectively induces NSD2 degradation in a cereblon- and proteasome-dependent fashion. (Blue: CRBN ligand , Black: linker ; Pink: NSD2 inhibitor ).
In SEM and RPMI-8402 cells, LLC0424 dose-dependently suppresses the growth of these two cell lines, with IC50 values of 3.56 μM and 0.56 μM respectively[1].LLC0424 (0.001 μM-10 μM; 1 h-24 h) induces NSD2 degradation in a concentration- and time-dependent manner, and induces NSD2 degradation in a CRBN- and proteasome-dependent manner. LLC0424 also leads to downregulation of H3K36Me2[1].
LLC0424 (60 mg/kg; iv or ip; for 5 consecutive days) shows potent NSD2 degradation in vivo[1].
References:
[1]. Lianchao Liu, et al. Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader. J Med Chem. 2024 May 9;67(9):6938-6951.