Golcadomide: An Oral CELMoD Agent Targeting IKZF1/3 For Diffuse Large B-Cell Lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with limited treatment options and poor prognosis, especially for patients refractory to standard therapies. We report the discovery of golcadomide (CC-99282), an oral cereblon-modulating CELMoD™ agent designed using target-specific knowledge and optimized pharmacological properties for the treatment of DLBCL. Golcadomide exhibited rapid, deep, and sustained degradation of transcription factors IKZF1 and IKZF3, surpassing the anti-tumor activity of the IMiD® agent lenalidomide in preclinical models. In human lymphoma cell lines, golcadomide downregulated MYC, activated interferon-stimulated genes, and promoted antiproliferation, apoptosis, and immunogenic cell death. In mouse xenografts, golcadomide preferentially distributed to tissues known to be affected by lymphoma, resulting in enhanced tumor regression and tumor-free outcomes. Pharmacological and CRISPR screening further revealed genes and pathways underlying golcadomide’s antitumor efficacy. These findings supported golcadomide as a promising drug candidate for DLBCL, providing a strong rationale for future golcadomide-based regimens.