Discovery of golcadomide (CC-99282) as a promising drug candidate for diffuse large B-cell lymphoma (DLBCL)
Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous disease with poor prognosis associated with high-risk molecular features. We report the discovery of golcadomide (CC-99282), a novel cereblon-modulating agent, that induces faster and deeper degradation of hematopoietic transcription factors Ikaros/Aiolos compared with first-generation degraders such as lenalidomide. In vitro, golcadomide induced interferon-stimulated genes, promoted apoptosis, robust antiproliferation, and immunogenic cell death, independent of clinical outcome determinators observed with standard care treatment. In vivo, golcadomide exhibited enhanced antitumor activity, resulting in significant tumor regression and tumor-free animals in lymphoma xenograft models. Pharmacological and CRISPR-based screenings demonstrated that targeting apoptosis, cell cycle progression, NF-kB signaling, and nuclear cytoplasmic transport increased antitumor efficacy of golcadomide. In summary, these data represent the discovery of golcadomide as a promising drug candidate for DLBCL and highlight the rationales for future golcadomide-based combination regimens that could improve clinical outcomes for patients. Overall design: Cleavage Under Targets and Release Using Nuclease (CUT&RUN)  for Ikaros and Aiolos in SUDHL-2 with DMSO vs compound treatment