Induction of protein degradation as a therapeutic strategy has been clinically validated by the class of immunomodulatory drugs that includes lenalidomide and pomalidomide, which are known to target Ikaros and Aiolos for degradation. In this session, we will disclose the discovery and structure of CC-99282, a CELMoD® agent that was specifically designed to address the unmet needs of patients with relapsed or refractory (R/R) lymphomas, who tend to have a poor prognosis and life expectancy. Our strategy to discover cereblon (CRBN) modulators with activity against R/R lymphomas was guided by both phenotypic data obtained in diffuse large B-cell lymphoma cells in culture and protein degradation data. As an additional strategy for obtaining optimal activity, we optimized for robust tissue distribution, including central nervous system penetration. CC-99282 drives the formation of a protein–protein interaction between zinc finger protein neosubstrates such as IKZF1/3 (Ikaros/Aiolos) and ZFP91 with CRBN. This interaction in turn induces targeted association of the respective neosubstrate to the CRL4CRBN E3 ubiquitin ligase complex. Thus, the CC-99282-dependent binding of neosubstrates to CRBN ultimately leads to polyubiquitination and proteasome-mediated degradation of neosubstrates that have been associated with clinical activity in multiple hematologic malignancies, including R/R lymphomas. In this presentation, a description of the structure–activity relationship, preclinical drug metabolism and pharmacokinetics, and efficacy data leading up to the discovery and selection of the novel protein degrader CC-99282 will be shared.

Discovery of CC-99282, a cereblon E3 ligase modulator (CELMoD) for the treatment of relapsed or refractory non-Hodgkin lymphomas and chronic lymphocytic leukemia/small lymphocytic lymphoma

ACS Fall 2021

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