Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma.

Autor:	Hansen JD; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Correa M; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Nagy MA; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Alexander M; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Plantevin V; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Grant V; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Whitefield B; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Huang D; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Kercher T; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Harris R; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Narla RK; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Leisten J; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Tang Y; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Moghaddam M; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Ebinger K; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Piccotti J; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Havens CG; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Cathers B; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Carmichael J; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Daniel T; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Vessey R; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Hamann LG; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Leftheris K; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Mendy D; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Baculi F; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., LeBrun LA; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Khambatta G; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States., Lopez-Girona A; Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Jul 09; Vol. 63 (13), pp. 6648-6676. Date of Electronic Publication: 2020 Mar 19.
DOI:	10.1021/acs.jmedchem.9b01928
Abstrakt:	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:	MEDLINE
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