Improved Pharmacokinetic Profiles of HDAC6 Inhibitors via Cap Group Modifications

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Structural Biology

Background:

• Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors often exhibit poor pharmacokinetic (PK) properties, hindering their therapeutic application.
• The cap group of HDAC inhibitors plays a crucial role in their efficacy and selectivity.

Purpose of the Study:

• To enhance the PK profile of the selective HDAC6 inhibitor TO-317 through cap group modification.
• To generate and evaluate novel HA-based HDAC inhibitors with improved in vivo performance.

Main Methods:

• Synthesis and characterization of 26 analogs of TO-317 with varied cap groups.
• Assessment of HDAC6 binding affinity and selectivity.
• X-ray crystallography to confirm key interactions.
• Pharmacokinetic studies in mice and preclinical efficacy testing in a melanoma model.

Main Results:

• Analog 14, with a 2-chlorobenzene sulfonamide cap, showed a 120-fold increase in plasma concentration compared to TO-317.
• Structural analysis confirmed the preservation of critical hydrogen bonds.
• Analog 14 achieved 56% tumor growth inhibition in a murine melanoma model with no observed toxicity.

Conclusions:

• Cap group optimization is an effective strategy to improve the PK profiles of HA-based HDAC inhibitors.
• Analog 14 represents a promising candidate for further preclinical and clinical development.
• Enhanced HDAC inhibitors hold potential for cancer therapy.