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

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: Dmax = 85%; DC50 = 257 nM).
Unlike our previously published cereblon-recruiting selective HDAC6
degrader, A6, which uses the same HDAC ligand, the FEM1B-based
PROTACs achieved selective HDAC1–3 degradation. This unexpected
change in the HDAC isoform degradation profile was accompanied by
significant enhancement of the antiproliferative properties.