A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos
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.
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SALL4 is degraded in the presence of pomalidomide and to a lesser extent by CC-220.
“Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [5]
Pomalidomide and CC-220 recruit and degrade IKZF1 along with SALL4 and several other targets.
“MGs can recruit or degrade more than one target; for example, pomalidomide (POM) and CC-220 recruit and degrade transcription factor IKZF1 along with SALL4 and several other targets3,5,6.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [5]
The weaker potencies observed for the interactions of SALL4 ZFs in the CRBN:CC-220 complex are consistent with previous reports of weaker degradation induced by this molecule.
“With respect to selectivity, the weaker potencies observed for the interactions of SALL4 ZFs in the CRBN:CC-220 complex are consistent with previous reports of weaker degradation induced by this molecule5.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [5]
CRBN appears to be emerging as a preferred E3 ligase for the first wave of TPD therapeutics in clinical trials.
“CRBN appears to be emerging as a preferred E3 ligase for the first wave of TPD therapeutics in clinical trials.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [73]
Iberdomide has a distinct chemical structure compared with other thalidomide analogues and might have a broader target specificity.
“Iberdomide has a distinct chemical structure compared with other thalidomide analogues (FIG. 1c) and might have a broader target specificity117.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often a C2H2 zinc finger domain, that binds to a composite thalidomide analogue-CRBN surface.
“Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often in the form of a Cys2-His2 (C2H2) zinc finger domain, that binds to a composite thalidomide analogue–CRBN surface17,117,121,167.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
Different thalidomide analogues mediate the degradation of overlapping but distinct sets of zinc finger domains.
“Notably, different thalidomide analogues mediate the degradation of overlapping but distinct sets of zinc finger domains117”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
These studies identified 11 individual zinc finger domains and six full-length zinc finger-containing proteins subject to drug-mediated degradation, and a larger number of zinc finger domains capable of binding to pomalidomide-engaged CRBN in vitro.
“These studies resulted in the identification of 11 individual zinc finger domains and six full-length zinc finger-containing that are subject to drug-mediated degradation, as well as a larger number of zinc finger domains that are capable of binding to pomalidomide-engaged CRBN in vitro117.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
Functional genomics approaches coupled with computational docking and in vitro binding analyses have been used to interrogate all human C2H2 zinc finger domains to define the zinc finger 'degrome' of thalidomide analogues.
“Functional genomics approaches coupled with computational docking and in vitro binding analyses have been used to interrogate all human C2H2 zinc finger domains in order to define the zinc finger ‘degrome’ of thalidomide analogues117.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
Crystallographic and saturation mutagenesis studies have identified amino acid residues of particular zinc finger domains that are crucial for their drug-induced recruitment to CRL4CRBN and subsequent degradation.
“Crystallographic and saturation mutagenesis studies have identified the amino acid residues of particular zinc finger domains that are crucial for their drug-induced recruitment to CRL4CRBN and subsequent degradation117”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
'Super-degron' tags composed of hybrid zinc finger degrons have been engineered to enhance the efficiency of drug-mediated degradation.
“To further develop this concept, ‘super-degron’ tags composed of hybrid zinc finger degrons have been engineered to enhance the efficiency of drug-mediated degradation117,207.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [117]
Treatment with C-220, a CRBN modulator that induces more potent degradation of IKZF1 and IKZF3 than previous IMiDs, elicits positive response in patients with systemic lupus erythematosus in a phase 2a study.
“treatment with C-220, a CRBN modulator that induces a more potent degradation of IKFZ1 and IKFZ3 than previous IMiDs 16 , elicits positive response in patients with systemic lupus erythematosus in a phase 2a study 17 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [16]
The clinical efficacy of IMiDs is driven at least in part by their capacity to induce CRBN-mediated degradation of neo-substrates.
“The clinical efficacy of IMiDs is driven at least in part by their capacity to induce CRBN-mediated degradation of neo-substrates: cancer cells become resistant to the multiple myeloma IMiD drug lenalidomide upon mutation of a single amino acid in IKFZ3 that rescues this transcription factor from proteolytic degradation 7 ;”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [16]
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- Authors
- 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.
- Affiliations
- 1Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
- Corresponding author
- Chamberlain, Philip P.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-04-20
- Volume
- 61
- Issue
- 2
- Pages
- 535-542
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2606131188
- Cited by
- 309
- References
- 28
- Citations by year
- 2026: 32 · 2025: 48 · 2024: 43 · 2023: 39 · 2022: 36 · 2021: 32 · 2020: 34 · 2019: 19 · 2018: 21 · 2017: 4 · 2016: 1
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Office of Science
- Argonne National Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- cereblon, Ikaros, Aiolos, lenalidomide, pomalidomide, targeted protein degradation, ubiquitination, protein degradation, DDB1, crystal structure, binding affinity, systemic lupus erythematosus, multiple myeloma
- MeSH terms
- Lenalidomide, DNA-Binding Proteins, Heterocyclic Compounds, 4 or More Rings, Humans, Morpholines, Multiple Myeloma, Peptide Hydrolases, Phthalimides, Piperidones, Protein Binding, Crystallography, X-Ray, Fluorescence Resonance Energy Transfer, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Proteolysis
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