Development of the first small molecule histone deacetylase 6 (HDAC6) degraders

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Histone deacetylases (HDACs) regulate protein acetylation and are implicated in various diseases, including cancers.
• Overexpression of HDACs contributes to disease pathogenesis.
• Targeted protein degradation using the ubiquitin-proteasome system (UPS) is a novel therapeutic strategy.

Purpose of the Study:

• To develop the first small molecule degraders for zinc-dependent HDACs.
• To create bifunctional molecules capable of selectively degrading HDAC6.
• To investigate the mechanism of targeted HDAC6 degradation.

Main Methods:

• Conjugation of non-selective HDAC inhibitors with E3 ubiquitin ligase ligands.
• Development of bifunctional molecules (dHDAC6).
• Cell-based assays to assess degradation efficacy.
• Mechanistic studies to elucidate the degradation pathway.

Main Results:

• Discovery of novel bifunctional molecules (dHDAC6) that selectively degrade HDAC6.
• Demonstration of targeted protein degradation of HDAC6 via the UPS.
• Identification of a new approach for targeting zinc-dependent HDACs.

Conclusions:

• Small molecule-mediated targeted protein degradation is effective for HDACs.
• HDAC6 can be selectively degraded using bifunctional molecules.
• This strategy offers a promising therapeutic avenue for HDAC-related diseases.