Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity

Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-Tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera (PROTAC) strategy, we previously developed the first HDAC6 degrader by tethering a pan HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multi-functional HDAC6 degraders by tethering selective HDAC6 inhibitor Next-A with CRBN ligand that can synergize with HDAC6 degradation for the anti-proliferation of multiple myeloma. This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising anti-proliferation activity in multiple myeloma (MM) cells.