Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4

Abstract

Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011). RDN8011 effectively degrades KDM4A-C while sparing KDM4D, and displays potent antiproliferative activity in esophageal cancer cells. Furthermore, this compound inhibits histone H3 lysine demethylation and induces cell cycle arrest and apoptosis. Collectively, this study provides a valuable chemical tool for exploring the functions of KDM4, and presents a novel effective strategy for targeting KDM4 in cancer treatment.