Related Experiment Video

Updated: Jun 8, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

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Cereblon-recruiting proteolysis targeting chimeras (PROTACs) can determine the selective degradation of HDAC1 over

Aline R Pavan1, Joshua P Smalley1, Urvashi Patel1

  • 1Leicester Institute of Structural and Chemical Biology and School of Chemistry, University of Leicester, University Road, Leicester, LE1 7RH, UK. JTHodgkinson@le.ac.uk.

Chemical Communications (Cambridge, England)
|November 5, 2024
PubMed

Insights

New PROTACs selectively degrade HDAC1 over HDAC3. These novel molecules offer a targeted approach to inhibiting histone deacetylase enzymes, unlike previous methods that primarily affected HDAC3.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Histone deacetylase (HDAC) enzymes 1-3 are implicated in various cellular processes and are recognized as potential drug targets.
  • Existing proteolysis targeting chimeras (PROTACs) for HDAC1-3 often show preferential degradation of HDAC3, limiting their specificity.

Purpose of the Study:

  • To develop novel cereblon-recruiting PROTACs capable of selectively degrading HDAC1.
  • To overcome the limitations of current PROTACs that target HDAC1-3 but primarily degrade HDAC3.

Main Methods:

  • Design and synthesis of novel cereblon-recruiting PROTAC molecules.
  • Biochemical assays to assess the degradation activity of PROTACs against HDAC1 and HDAC3.

Main Results:

  • The developed PROTACs effectively recruit cereblon.
  • These PROTACs demonstrate selective degradation of HDAC1 in the presence of HDAC3.
  • Achieved degradation of HDAC1 with high selectivity over HDAC3.

Conclusions:

  • Successfully developed PROTACs that achieve selective HDAC1 degradation.
  • These findings present a new strategy for targeting HDAC1 specifically, offering potential therapeutic advantages over existing methods.

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