Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells

Abstract

Histone lysine-specific demethylase 5B (KDM5B) is frequently overexpressed in a wide range of tumors and is regarded as a promising target for drug development. Current drugs targeting KDM5B are primarily small-molecule inhibitors, which suffer from limitations such as poor selectivity and insufficient pharmacological efficacy. Targeted protein degradation (TPD) technology as an emerging drug development strategy has received extensive attention in recent years, that enables the catalytic elimination of the entire protein of interest, thereby disrupting both the enzymatic and non-enzymatic functions. Herein, we investigated a series of novel KDM5B degraders by tethering the KDM5B inhibitor GSK467 to various recruiters that tried to mediate protein degradation via the ubiquitin-proteasome or autophagy-lysosome pathway. Among these, the representative compound YTHu78 effectively induced KDM5B degradation through the ubiquitin-proteasome system and triggered lytic apoptosis in MV-4-11 and MM.1S cell lines. Moreover, YTHu78 demonstrated notable antiproliferative activities against several hematologic malignancy cell lines. In contrast, the KDM5B inhibitor GSK467 neither showed antiproliferative activities in the tested hematologic malignancy cell lines nor induced cell apoptosis. These findings underscore the distinct biological functional differences between the KDM5B degrader and inhibitor. YTHu78 serves as a valuable chemical tool for further exploration of KDM5B's biological roles, and the development of KDM5B-targeted degraders may represent a promising therapeutic strategy for hematologic malignancies in the future.

Keywords: Hematological malignancy; KDM5B; PROTAC; TPD.