
Designing HDAC-PROTACs: lessons learned so far
Author(s) -
Fabian Fischer,
Leandro A. Alves Avelar,
Laoise Murray,
Thomas Kurz
Publication year - 2022
Publication title -
future medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.708
H-Index - 69
eISSN - 1756-8927
pISSN - 1756-8919
DOI - 10.4155/fmc-2021-0206
Subject(s) - histone deacetylase , ubiquitin ligase , proteasome , drug discovery , computational biology , ubiquitin , protein degradation , drug , proteolysis , pharmacology , biology , chemistry , histone , microbiology and biotechnology , bioinformatics , biochemistry , dna , gene , enzyme
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.