Lier, Svenja and Sellmer, Andreas and Orben, Felix and Heinzlmeir, Stephanie and Krauss, Lukas and Schneeweis, Christian and Hassan, Zonera and Schneider, Carolin and Schaefer, Arlett Patricia Gloria and Pongratz, Herwig and Engleitner, Thomas and Oellinger, Rupert and Kuisl, Anna and Bassermann, Florian and Schlag, Christoph and Kong, Bo and Dove, Stefan and Kuster, Bernhard and Rad, Roland and Reichert, Maximilian and Wirth, Matthias and Saur, Dieter and Mahboobi, Siavosh and Schneider, Gunter (2022) A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer. BIOORGANIC CHEMISTRY, 119: 105505. ISSN 0045-2068, 1090-2120
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SELECTIVE DEGRADATION; PROTEIN-DEGRADATION; TARGET; MYC; PROTEOLYSIS; GSPT1; Cereblon; GSPT1; GSPT2; MYC; PLK1 |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Jan 2024 13:43 |
| Last Modified: | 31 Jan 2024 13:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58270 |
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