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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The application of PROTAC in HDAC.
Eur J Med Chem
November 2023
Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address:
Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1-8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs.
View Article and Find Full Text PDFA 'click' chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras.
RSC Med Chem
December 2022
Leicester Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester Leicester LE1 7RH UK
Click chemistry was utilised to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. A novel PROTAC JMC-137 was identified as a HDAC1/2 and HDAC3 degrader in HCT116 cells. However, potency was compromised compared to previously identified class I HDAC PROTACs highlighting the importance in the choice of HDAC ligand, functional group for linker attachment and positioning in PROTAC design.
View Article and Find Full Text PDFDesigning HDAC-PROTACs: lessons learned so far.
Future Med Chem
January 2022
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr 1, Düsseldorf, 40225, Germany.
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.
View Article and Find Full Text PDFDesign, Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands.
Molecules
November 2021
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types.
View Article and Find Full Text PDFAdvances in the Design and Development of PROTAC-mediated HDAC Degradation.
Curr Top Med Chem
March 2022
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Due to developments in modern chemistry, previously uundruggable substrates are now targetable thanks to selective degradation using the ubiquitin-proteasomal degradation system. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically to degrade target proteins. They are of significant interest to industry and academia as they are highly specific and can target previously undruggable target proteins from transcription factors to enzymes.
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