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Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3, respectively) are members of the Ikaros family of zinc-finger transcription factors and are responsible for lymphocyte differentiation and B-cell development.1,2 Genome-wide association studies have shown that polymorphisms in IKZF1 and IKZF3 correlated with an increased risk for developing systemic lupus erythematosus (SLE),1-4 and Ikaros and Aiolos were overexpressed in the peripheral blood of patients with SLE, as compared to healthy controls.1,2 Aiolos is required for the production of long-lived, high-affinity plasma cells and Ikaros may play a role in the development of plasmacytoid dendritic cells.1,2
Ikaros and Aiolos are substrates of the cullin ring ligase 4 (CRL4CRBN) E3 ubiquitin ligase complex.5 Cereblon (CRBN) is the target protein receptor on CRL4CRBN that includes cullin 4A (CUL4), DNA damage-binding protein 1 (DBB1), and regulator of cullin 1 (ROC1).1,6 Preclinical studies suggest that immunomodulatory agents can co-opt CRBN and modulate its function to redirect target proteins for ubiquitination and proteasomal degradation.5,7,8 Ikaros and Aiolos are recruited to CRL4CRBN in T cells for proteasomal degradation.5
Based on preclinical studies, the roles of Ikaros and Aiolos in the regulation and homeostasis of the immune system suggest that CRBN may be redirected for therapeutic purposes in immune-mediated disorders such as SLE.
AutoAbs, autoantibodies CRBN, cereblon; CRL4, cullin ring ligase 4; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IgG, immunoglobulin G; IgM, immunoglobulin M; IL, interleukin; IM, immunoglobulin TNF, tumor necrosis factor