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Discovery of golcadomide (CC-99282) as a promising drug candidate for diffuse large B-cell lymphoma (DLBCL)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262641 | GEO | 2025/10/10

REPOSITORIES: GEO

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CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

Project description:Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of two common substrates, transcription factors Aiolos and Ikaros. Here we report that the pleiotropic pathway modifier CC-122, a new chemical entity termed pleiotropic pathway modifier binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or shRNA mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon stimulated genes (ISGs) independent of interferon Î±, Î², Î³ production and/or secretion and results in apoptosis in both ABC and GCB-DLBCL cell lines. Our results provide mechanistic insight into the cell of origin independent anti-lymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide. Microarray analysis of the OCI-LY10 activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell line treated with the compound CC-122 for 18 hours

2015-11-26 | E-GEOD-75420 | biostudies-arrayexpress

CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

Project description:Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of two common substrates, transcription factors Aiolos and Ikaros. Here we report that the pleiotropic pathway modifier CC-122, a new chemical entity termed pleiotropic pathway modifier binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or shRNA mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon stimulated genes (ISGs) independent of interferon α, β, γ production and/or secretion and results in apoptosis in both ABC and GCB-DLBCL cell lines. Our results provide mechanistic insight into the cell of origin independent anti-lymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.

2015-11-26 | GSE75420 | GEO

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Discovery of golcadomide (CC-99282) as a promising drug candidate for diffuse large B-cell lymphoma (DLBCL)

Project description:Discovery of golcadomide (CC-99282) as a promising drug candidate for diffuse large B-cell lymphoma (DLBCL)

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