Related Experiment Video

Updated: Oct 11, 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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A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

Svenja Lier1, Andreas Sellmer2, Felix Orben1

  • 1Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany.

Bioorganic Chemistry
|November 28, 2021
PubMed

Insights

Researchers developed a novel PROTAC (proteolysis targeting chimera) called MDEG-541 to degrade MYC oncoproteins. This targeted protein degradation approach showed sensitivity in gastrointestinal cancer models, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation is a promising strategy for inactivating cancer drivers.
  • Proteolysis targeting chimera (PROTAC) and Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs) are key technologies in this field.

Purpose of the Study:

  • To develop a MYC PROTAC (proteolysis targeting chimera), MDEG-541, utilizing a MYC-MAX dimerization inhibitor derivative and Thalidomide.
  • To evaluate the efficacy of MDEG-541 in gastrointestinal cancer models.

Main Methods:

  • Development of MDEG-541, a PROTAC targeting MYC.
  • Testing MDEG-541 sensitivity in gastrointestinal cancer cell lines and patient-derived organoids.
  • Investigating the mechanism of MYC degradation, including CRBN, proteasome, and ubiquitin dependence.

Main Results:

  • MDEG-541 demonstrated sensitivity in a subset of gastrointestinal cancer cell lines and organoids.
  • MYC degradation was dependent on CRBN, the proteasome, and ubiquitin.
  • MDEG-541 induced degradation of CRBN neosubstrates, including GSPT1/2 and PLK1.

Conclusions:

  • A novel CRBN-dependent degrader, MDEG-541, targeting MYC was successfully established.
  • MDEG-541 exhibits activity in gastrointestinal cancers, highlighting its therapeutic potential.
Keywords:
CereblonGSPT1GSPT2MYCPLK1

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