E3 ligase hopping and more: development of covalent class I selective HDAC degraders with potent anticancer activity

Histone deacetylases (HDACs) are intriguing targets for tumor therapy due to their high expression in many tumor entities. For example, in hematological malignancies, HDAC overexpression is associated with poor prognosis. Furthermore, the inhibition of HDAC activity leads to differentiation, decreased migration, and angiogenesis of cancer cells as well as sensitizes tumors to chemotherapy.

Proteolysis-Targeting Chimeras (PROTACs) represent a revolutionary paradigm shift in the field of drug discovery. They own multiple advantages over classical inhibitors like a catalytic mode of action and prolongated pharmacological effects by hijacking the ubiquitin-proteasome system. So far, the targeted degradation of HDACs by PROTACs is only facilitated through the recruitment of the well-studied von Hippel-Lindau (VHL), inhibitor of apoptosis protein (IAP), and cereblon (CRBN) E3 ligases. Thus, there is an urgent need to utilize other E3 ligases for HDAC degradation. This need is further documented by the susceptibility of PROTACs to resistance development in tumor cells and offers the chance for new selectivity profiles.

In this study, we report the discovery of the first-in-class protein fem-1 homolog B (FEM1B)-recruiting HDAC PROTACs. The synthesis was performed using solid-phase synthesis, starting with Fmoc-protected preloaded resins. This was followed by the attachment of cap groups and linkers, and completed by introducing a covalent FEM1B warhead. Biological assessment showed that replacing the thalidomide-based CRBN ligand in our previously published selective HDAC6 PROTAC A6 [1] with a covalent FEM1B ligand led to highly selective HDAC1-3 degraders. This unexpected change in HDAC isoform degradation profiles was accompanied by a significant enhancement of the anticancer properties.