Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cancer Biology

Background:

• Previous research developed phenylsulfonylfuroxan-based hydroxamates with antitumor properties.
• Compound 1 showed potent antitumor activity via histone deacetylase (HDAC) inhibition and nitric oxide (NO) donation.

Purpose of the Study:

• To investigate the mechanism of action of compound 1, focusing on its irreversible inhibition of HDACs.
• To develop a novel, selective, and irreversible HDAC6 inhibitor based on compound 1.
• To evaluate the efficacy and therapeutic index of the novel inhibitor against multiple myeloma.

Main Methods:

• In-depth mechanistic studies of compound 1's HDAC inhibition.
• Structure-activity relationship studies leading to compound 4.
• In vitro and in vivo assays to assess HDAC6 inhibition, anti-multiple myeloma activity, and therapeutic index.

Main Results:

• Compound 1 irreversibly inhibits class I HDACs and HDAC6, increasing acetyl histones and acetyl α-tubulin.
• Compound 4, a novel hydroxamate, selectively and irreversibly inhibits intracellular HDAC6.
• Compound 4 demonstrated superior anti-multiple myeloma efficacy and an improved therapeutic index compared to ACY-241.

Conclusions:

• This research reports the first instance of irreversible HDAC6 inhibition.
• Compound 4 represents a promising novel therapeutic agent for multiple myeloma due to its selective and irreversible HDAC6 inhibition.
• The findings suggest potential for improved cancer treatment strategies targeting HDAC6.