Induction of protein degradation as a therapeutic strategy has been clinically validated by the class of immunomodulatory drugs lenalidomide and pomalidomide which are known to target Ikaros/Aiolos for degradation. In this session, we will disclose the structure of CC-92480, a CELMoD that was specifically designed to address relapsed and refractory multiple myeloma (RRMM). CC-92480 drives the formation of a protein–protein interaction between zinc finger proteins such as Ikaros and Aiolos with cereblon (CRBN), which induces targeted docking to the CRL4<sup>CRBN</sup> E3 ubiquitin ligase complex. The CC-92480-dependent binding of Ikaros/Aiolos to CRBN leads to polyubiquitination and ultimately proteasome-mediated degradation of Ikaros/Aiolos. Our strategy to discover cereblon modulators with activity against RRMM employed an approach guided by both phenotypic and protein degradation data. In this presentation, a description of, the SAR, preclinical DMPK, and efficacy data leading up to the discovery and selection of the novel protein degrader, CC-92480 will be shared.

Discovery of CC-92480: CRBN E3 ligase modulating drug (CELMoD) for the treatment of relapsed and refractory multiple myeloma

2019 Fall National Meeting

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