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 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 multifunctional
HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat
A with CRBN ligand that can synergize with HDAC6 degradation for the
antiproliferation of multiple myeloma (MM). 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 antiproliferation activity in multiple myeloma (MM)
cells.