Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• Histone deacetylase 6 (HDAC6) removes acetyl groups from cytoplasmic proteins like α-tubulin and HSP90.
• HDAC6 plays a role in various disease-related pathways.
• Previous work established the first HDAC6 degrader using a proteolysis targeting chimera (PROTAC) strategy.

Purpose of the Study:

• To develop a new generation of multifunctional HDAC6 degraders.
• To enhance antiproliferative activity against multiple myeloma (MM) by combining HDAC6 inhibition and degradation.
• To optimize degrader design for improved potency and selectivity.

Main Methods:

• Utilized a PROTAC strategy tethering a selective HDAC6 inhibitor (Nexturastat A) with a cereblon (CRBN) E3 ubiquitin ligase ligand.
• Synthesized and optimized novel HDAC6 degraders by modifying linker length and attachment points.
• Assessed degrader potency (DC50) and antiproliferative effects in MM cell lines.

Main Results:

• Developed novel multifunctional HDAC6 degraders with improved potency and selectivity.
• Achieved nanomolar DC50 values for HDAC6 degradation.
• Demonstrated promising antiproliferation activity in multiple myeloma cells.

Conclusions:

• The new class of HDAC6 degraders synergizes HDAC6 inhibition and degradation for potent MM cell killing.
• Optimized degrader design led to highly effective compounds for targeting HDAC6.
• These findings offer a promising therapeutic strategy for multiple myeloma.