Development of the First-in-Class FEM1B-Recruiting Histone Deacetylase Degraders.

ABSTRACT: Targeted protein degradation (TPD) represents a promising alternative to conventional occupancy-driven protein inhibition. Despite the existence of more than 600 E3 ligases in the human proteome, so far only a few have been utilized for TPD of histone deacetylases (HDACs), which represent important epigenetic anticancer drug targets. In this study, we disclose the first-in-class Fem-1 homologue B (FEM1B)-recruiting HDAC degraders. A set of 12 proteolysis targeting chimeras (PROTACs) was synthesized using a solid-phase supported parallel synthesis approach utilizing a covalent FEM1B ligand as an E3 ligase warhead. The evaluation of the HDAC degradation efficiency revealed substantial HDAC1 degradation by the top-performing degrader FF2049 (1g: D_max = 85%; DC<

SUBMITTER: Feller F 

PROVIDER: S-EPMC11780399 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature