Designing HDAC-PROTACs: lessons learned so far

Area of Science:

• Chemical biology
• Drug discovery
• Oncology

Background:

• Proteolysis-targeting chimeras (PROTACs) leverage the ubiquitin-proteasome system for targeted protein degradation.
• Histone deacetylase inhibitors (HDACi) are established treatments for hematological malignancies.
• PROTACs present a new paradigm in drug design, distinct from traditional mechanisms.

Purpose of the Study:

• To review the structural development of HDAC-PROTACs.
• To explore the potential of targeted chemical degradation of HDACs.
• To provide a perspective on optimizing HDAC-PROTAC efficacy and selectivity.

Main Methods:

• Review of existing literature on PROTAC technology and HDAC inhibitors.
• Analysis of the structural components of HDAC-PROTACs: HDAC inhibitor, linker, and E3 ligase ligand.
• Discussion of structure-activity relationships influencing degradation efficacy and selectivity.

Main Results:

• PROTACs offer a promising approach for targeted protein degradation, with some agents advancing to clinical trials.
• Integration of HDAC binding motifs into PROTACs enables targeted degradation of HDACs.
• The efficacy and selectivity of HDAC-PROTACs are significantly influenced by the choice of HDACi, linker, and E3 ligase ligand.

Conclusions:

• HDAC-PROTACs represent a significant advancement in targeted cancer therapy, offering a novel degradation mechanism.
• Optimization of the three core PROTAC components is crucial for developing effective and selective HDAC degraders.
• Further research into HDAC-PROTAC structure development holds promise for treating hematological malignancies and potentially other cancers.