DCAF16-Based Covalent Molecular Glues for Targeted Protein Degradation of Histone Deacetylases.

Histone deacetylases (HDACs) are intriguing cancer targets due to their high expression in many tumors. Consequently, inhibition or degradation of HDACs can be beneficial for cancer therapy. Targeted protein degradation using molecular glues represents a promising therapeutic approach, enabling the specific degradation of numerous disease-causing proteins. However, the rational design of molecular glues in a target-based manner remains challenging. A recent study has described the identification of a DCAF16-based covalent linker-less chemical handle for molecular glues. This covalent warhead can be attached to protein of interest ligands to induce the targeted degradation of various protein classes. Inspired by this, we designed and synthesized a new class of DCAF16-based covalent molecular glues utilizing different zinc-binding groups for the targeted degradation of HDACs. This approach led to the discovery of an efficient molecular glue (10a) that reduced HDAC1 levels in multiple myeloma MM.1S cells in a potent and preferential manner.