Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
Abstract
Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
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CC-92480 (224) is a protein degrader with potential for treating MM, derived from lenalidomide, binding to CRBN and leading to degradation of TFs such as Ikaros and Aiolos; more efficient Aiolos degradation correlates with faster death of MM cell lines, including lenalidomide- and pomalidomide-resistant lines, and it exhibits potent immunostimulatory activity.
“Joshua D. Hansen’s research team has developed CC-92480 (224), a protein degrader with potential for treating MM (Table 4). Derived from lenalidomide, this therapy binds to the E3 ubiquitin ligase CRBN, leading to the degradation of TFs such as Ikaros and Aiolos. In cell culture assays, the researchers observed that the more efficiently CC-92480 degraded Aiolos, the faster it induced the death of”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [528]
A screen for IMiD-induced cytotoxicity in cells with low CRBN levels revealed the highly potent IMiD CC-92480.
“Similarly, a straightforward screen for IMiD-induced cytotoxicity in cells with low CRBN levels revealed the highly potent IMiD CC-92480,167 which has recently entered clinical investigation.”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [167]
Molecular glues constitute another important therapeutic class of targeted protein degraders.
“Molecular glues, based on the serendipitous discovery that thalidomide and its analogues act as degrader molecules, constitute another important therapeutic class1–8.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [2]
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- Authors
- Hansen, J. D., Correa, M., Nagy, M. A., Alexander, M., Plantevin, V., Grant, V., Whitefield, B., Huang, D., Kercher, T., Harris, R., Narla, R. K., Leisten, J., Tang, Y., Moghaddam, M., Ebinger, K., Piccotti, J., Havens, C. G., Cathers, B., Carmichael, J., Daniel, T., Vessey, R., Hamann, L. G., Leftheris, K., Mendy, D., Baculi, F., LeBrun, L. A., Khambatta, G., & Lopez-Girona, A.
- Affiliations
- Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States
- Corresponding author
- Hansen, Joshua D.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-03-04
- Volume
- 63
- Issue
- 13
- Pages
- 6648-6676
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W3010457103
- Cited by
- 240
- References
- 20
- Citations by year
- 2026: 38 · 2025: 48 · 2024: 43 · 2023: 37 · 2022: 34 · 2021: 33 · 2020: 7
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- cereblon E3 ligase modulator, CELMoD, relapsed/refractory multiple myeloma, lenalidomide resistance, protein degradation, degradation kinetics, degradation efficiency, lenalidomide, proteasome inhibitors, immunomodulators, drug discovery
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Multiple Myeloma, Recurrence, Stereoisomerism, Treatment Failure, Inhibitory Concentration 50, Xenograft Model Antitumor Assays, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice
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