A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos
Top Cited Papers
- 25 January 2018
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 61 (2), 535-542
- https://doi.org/10.1021/acs.jmedchem.6b01921
Abstract
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.This publication has 28 references indexed in Scilit:
- Rate of CRL4CRBN substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4Blood Cancer Journal, 2015
- Current treatment landscape for relapsed and/or refractory multiple myelomaNature Reviews Clinical Oncology, 2014
- The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros ProteinsScience, 2014
- Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma CellsScience, 2014
- Immunomodulatory agents lenalidomide and pomalidomide co‐stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBNBritish Journal of Haematology, 2013
- Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomideLeukemia, 2012
- Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomideBlood, 2011
- The Ikaros gene family: Transcriptional regulators of hematopoiesis and immunityMolecular Immunology, 2011
- Identification of a Primary Target of Thalidomide TeratogenicityScience, 2010
- The role of Ikaros in human erythroid differentiationBlood, 2008