4.5 Review

Designing HDAC-PROTACs: lessons learned so far

期刊

FUTURE MEDICINAL CHEMISTRY
卷 14, 期 3, 页码 143-166

出版社

Newlands Press Ltd
DOI: 10.4155/fmc-2021-0206

关键词

epigenetics; histone deacetylases; PROTAC; protein degradation; ubiquitin proteasome system

资金

  1. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [GRK 2158]
  2. Deutscher Akademischer Austauschdienst (DAAD, German Academic Exchange Service)

向作者/读者索取更多资源

PROTACs are a powerful tool for degrading intracellular proteins by hijacking the UPS system, with potential for targeted HDAC degradation. This review discusses the key factors in the development of HDAC-PROTACs, including HDACi, linker, and E3 ligase ligand, and their impact on efficacy and selectivity.
Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into Phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC-PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC-PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.

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