5V3O

Cereblon in complex with DDB1 and CC-220

Summary for 5V3O

• Entry DOI: 10.2210/pdb5v3o/pdb
• Descriptor: DNA damage-binding protein 1, Protein cereblon, (3S)-3-[4-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione, ... (4 entities in total)
• Functional Keywords: e3, ubiquitin ligase, crl4, dcaf, ligase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: Q16531 Q96SW2
• Total number of polymer chains: 2
• Total formula weight: 174208.94

Authors

Matyskiela, M.,Pagarigan, B.,Chamberlain, P. (deposition date: 2017-03-07, release date: 2017-05-03, Last modification date: 2024-11-13)

Primary citation

Matyskiela, M.E.,Zhang, W.,Man, H.W.,Muller, G.,Khambatta, G.,Baculi, F.,Hickman, M.,LeBrun, L.,Pagarigan, B.,Carmel, G.,Lu, C.C.,Lu, G.,Riley, M.,Satoh, Y.,Schafer, P.,Daniel, T.O.,Carmichael, J.,Cathers, B.E.,Chamberlain, P.P.
A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos.
J. Med. Chem., 61:535-542, 2018

PubMed 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.

PubMed: 28425720
DOI: 10.1021/acs.jmedchem.6b01921

Experimental method

X-RAY DIFFRACTION (3.2 Å)