Shifting the paradigm in treating multi-factorial diseases: polypharmacological co-inhibitors of HDAC6

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Multi-factorial diseases involve complex cellular processes, often rendering single-target therapies ineffective due to resistance.
• Combination therapies are standard but face challenges like poor patient compliance, narrow therapeutic windows, and high costs.
• Polypharmacology, using single drugs to hit multiple targets, emerges as a superior alternative to combination therapy.

Purpose of the Study:

• To explore the development of polypharmacological agents for treating multi-factorial diseases.
• To focus on Histone Deacetylase 6 (HDAC6) as a key therapeutic target.
• To design novel therapeutics by combining HDAC pharmacophores with other target-specific moieties.

Main Methods:

• Rational drug design integrating HDAC pharmacophores with other target-binding elements.
• Emphasis on achieving selectivity for HDAC6.
• Exploration of synergistic effects of multi-target agents.

Main Results:

• Recent efforts have focused on merging HDAC pharmacophores with other target pharmacophores.
• The goal is to create potent therapeutics with improved efficacy for complex diseases.
• Polypharmacological agents show potential for inherent synergism.

Conclusions:

• Polypharmacology offers a promising strategy to overcome limitations of current treatments for multi-factorial diseases.
• Targeting HDAC6 with polypharmacological agents could lead to novel therapies for Alzheimer's disease and cancer.
• These agents may offer reduced dosing, wider therapeutic windows, and improved patient compliance compared to combination therapies.