Discovery of LLC0424 as a Potent and Selective <i>in Vivo</i> NSD2 PROTAC Degrader.

ABSTRACT: Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC₅₀ value of 20 nM and a D_max value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively indu

SUBMITTER: Liu L 

PROVIDER: S-EPMC11094793 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature