cc-122 and pomalidomide

Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, 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 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that 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 short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; B-Lymphocytes; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Ikaros Transcription Factor; Interferon Regulatory Factor-7; Interferons; Lenalidomide; Lentivirus; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, SCID; Molecular Mimicry; Peptide Hydrolases; Piperidones; Proteolysis; Quinazolinones; RNA, Small Interfering; Signal Transduction; T-Lymphocytes; Thalidomide; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays