CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia
Abstract
Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.
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The discovery of CC-885 as a CRBN-dependent GSPT1 degrader was initially motivated by cancer cell line profiling studies.
“The discovery of CC-885 as a CRBN-dependent GSPT1 degrader53 was likewise initially motivated by cancer cell line profiling studies, prompting the development of the clinical candidate CC-90009.168,169”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [169]
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- Authors
- Hansen, J. D., Correa, M., Alexander, M., Nagy, M., Huang, D., Sapienza, J., Lu, G., LeBrun, L. A., Cathers, B. E., Zhang, W., Tang, Y., Ammirante, M., Narla, R. K., Piccotti, J. R., Pourdehnad, M., & Lopez-Girona, A.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- Bristol Myers Squibb, 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
- 2021-02-16
- Volume
- 64
- Issue
- 4
- Pages
- 1835-1843
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W3130685989
- Cited by
- 159
- References
- 20
- Citations by year
- 2026: 27 · 2025: 45 · 2024: 30 · 2023: 23 · 2022: 22 · 2021: 11 · 2014: 1
- FWCI
- 6.99
- 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 › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- cereblon E3 ligase modulator, GSPT1, acute myeloid leukemia, selective protein degradation, proteasomal degradation, targeted protein degradation, relapsed/refractory AML, pharmacokinetics, mechanism of action
- MeSH terms
- Acetamides, Animals, Antineoplastic Agents, Humans, Macaca fascicularis, Male, Peptide Termination Factors, Piperidones, Structure-Activity Relationship, Molecular Structure, Leukemia, Myeloid, Acute, Apoptosis, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Isoindoles, Proteolysis
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