Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Histone deacetylase 6 (HDAC6) overexpression is implicated in multiple cancer hallmarks, including tumor growth, invasion, and survival.
• HDAC6 is a promising anticancer target, but conventional inhibitors face challenges like limited efficacy and resistance.
• Non-enzymatic functions of HDAC6 also contribute to cancer progression, necessitating novel therapeutic approaches.

Purpose of the Study:

• To review recent advances in the design and development of HDAC6 modulators for cancer therapy.
• To explore novel strategies including isoform-selective inhibitors, dual-target inhibitors, and targeted protein degraders (TPD).
• To discuss the rational design, pharmacodynamics, pharmacokinetics, and clinical status of these emerging HDAC6-based therapies.

Main Methods:

• Literature review of recent research on HDAC6 inhibitors and modulators.
• Analysis of rational design principles for developing new HDAC6-targeting agents.
• Evaluation of pharmacodynamic and pharmacokinetic properties of novel HDAC6 inhibitors.
• Assessment of the clinical status and future potential of HDAC6-based drug discovery.

Main Results:

• HDAC6 plays a critical role in cancer initiation and progression.
• Conventional HDAC6 inhibitors exhibit limitations in clinical efficacy and resistance.
• Emerging strategies like dual-acting inhibitors and TPD (PROTACs, HyT) offer enhanced anticancer activity.
• Isoform-selective and dual-target inhibitors represent promising avenues for cancer treatment.

Conclusions:

• Novel HDAC6 modulators, including dual-target inhibitors and TPD, are essential to overcome limitations of current therapies.
• Rational design and understanding of pharmacodynamics/pharmacokinetics are crucial for developing effective HDAC6-based cancer drugs.
• Further research and clinical investigation are needed to fully realize the therapeutic potential of HDAC6 targeting in oncology.