2. Academic Validation
  3. A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

  • Bioorg Chem. 2022 Feb;119:105505. doi: 10.1016/j.bioorg.2021.105505.
Svenja Lier 1,  Andreas Sellmer 2,  Felix Orben 1,  Stephanie Heinzlmeir 3,  Lukas Krauß 1,  Christian Schneeweis 1,  Zonera Hassan 1,  Carolin Schneider 1,  Arlett Patricia Gloria Schäfer 1,  Herwig Pongratz 2,  Thomas Engleitner 4,  Rupert Öllinger 4,  Anna Kuisl 5,  Florian Bassermann 6,  Christoph Schlag 1,  Bo Kong 7,  Stefan Dove 2,  Bernhard Kuster 8,  Roland Rad 9,  Maximilian Reichert 10,  Matthias Wirth 11,  Dieter Saur 12,  Siavosh Mahboobi 13,  Günter Schneider 14
Affiliations

Affiliations

  • 1 Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany.
  • 2 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
  • 3 Chair of Proteomics and Bioanalytics, TU Munich, 85354 Freising, Germany.
  • 4 Institute of Molecular Oncology and Functional Genomics, MRI, TU Munich, Germany.
  • 5 Medical Clinic and Policlinic III, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany.
  • 6 Medical Clinic and Policlinic III, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
  • 7 Department of Surgery, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; Department of General Surgery, University of Ulm, 89081 Ulm, Germany.
  • 8 Chair of Proteomics and Bioanalytics, TU Munich, 85354 Freising, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), TU Munich, 85354 Freising, Germany.
  • 9 Institute of Molecular Oncology and Functional Genomics, MRI, TU Munich, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
  • 10 Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Center for Protein Assemblies (CPA), Technische Universität München, 85747 Garching, Germany.
  • 11 Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, 12203 Berlin, Germany.
  • 12 German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Institute for Translational Cancer Research and Experimental Cancer Therapy, Klinikum Rechts der Isar, TU Munich, Germany.
  • 13 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany. Electronic address: siavosh.mahboobi@ur.de.
  • 14 Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany; University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, 37075 Göttingen, Germany. Electronic address: guenter.schneider@med.uni-goettingen.de.
PMID: 34838332 DOI: 10.1016/j.bioorg.2021.105505
Abstract

Targeted protein degradation offers new opportunities to inactivate Cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 Ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal Cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant Cancer targets with activity in gastrointestinal cancers.

Keywords

Cereblon; GSPT1; GSPT2; MYC; PLK1.

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