Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
| Autor: | Courtney G. Havens, Correa Matthew D, Rama K. Narla, Frans Baculi, Kercher Timothy S, Thomas O. Daniel, Roy L. Harris, Brian E. Cathers, Matt Alexander, Mehran F. Moghaddam, Grant Virginia Heather Sharron, Veronique Plantevin, James Carmichael, Katalin Ebinger, Antonia Lopez-Girona, Gody Khambatta, Derek Mendy, Lawrence G Hamann, Joshua Hansen, Katerina Leftheris, Brandon Wade Whitefield, Joseph Piccotti, Nagy Mark A, Rupert Vessey, Yang Tang, Laurie LeBrun, Jim Leisten, Dehua Huang |
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| Rok vydání: | 2020 |
| Předmět: |
Oncology
medicine.medical_specialty Ubiquitin-Protein Ligases Antineoplastic Agents Protein degradation 01 natural sciences Inhibitory Concentration 50 Mice 03 medical and health sciences Refractory Recurrence Cell Line Tumor Internal medicine Drug Discovery medicine Animals Humans Treatment Failure Multiple myeloma Adaptor Proteins Signal Transducing Cell Proliferation 030304 developmental biology Lenalidomide 0303 health sciences biology Chemistry Cereblon Stereoisomerism Pomalidomide medicine.disease Xenograft Model Antitumor Assays 0104 chemical sciences Ubiquitin ligase 010404 medicinal & biomolecular chemistry Proteasome biology.protein Molecular Medicine Female Multiple Myeloma medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 63:6648-6676 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01928 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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