A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos
| Autor: | Yoshitaka Satoh, Gilles Carmel, Frans Baculi, Peter H. Schafer, Laurie LeBrun, Matt Hickman, Thomas O. Daniel, Brian E. Cathers, James Carmichael, Godrej Khambatta, Hon-Wah Man, Mary E Matyskiela, Philip P Chamberlain, Weihong Zhang, Mariko Riley, George W. Muller, Barbra Pagarigan, Gang Lu, Chin-Chun Lu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Morpholines Ubiquitin-Protein Ligases Phthalimides Crystallography X-Ray Heterocyclic Compounds 4 or More Rings Ikaros Transcription Factor 03 medical and health sciences DDB1 0302 clinical medicine Cell Line Tumor Drug Discovery Fluorescence Resonance Energy Transfer medicine Humans Binding site Lenalidomide Transcription factor Piperidones Adaptor Proteins Signal Transducing chemistry.chemical_classification DNA ligase biology Cereblon Protein Cereblon Pomalidomide Molecular biology Ubiquitin ligase Cell biology DNA-Binding Proteins 030104 developmental biology chemistry 030220 oncology & carcinogenesis Proteolysis biology.protein Molecular Medicine Multiple Myeloma Peptide Hydrolases Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 61:535-542 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater. The crystal structure of cereblon in complex with DDB1 and compound 6 reveals that the increase in potency correlates with increased contacts between compound 6 and cereblon away from the modeled binding site for Ikaros/Aiolos. These results describe a new cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase and provides an example of the effect of E3 ligase binding affinity with relevance to other drug discovery efforts in targeted protein degradation. |
| Databáze: | OpenAIRE |
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