Cereblon/E3 Ligase Pathway

Cereblon (CRBN) is a component of an E3 ubiquitin ligase complex (CRL4CRBN) that includes Cul4, DDB1, and Roc1.1-3 CRBN is expressed in a variety of tissues, with the highest levels detected in T and B cells among other immune cells.4,5 Preclinical studies suggest that binding of the immunomodulatory agents lenalidomide and pomalidomide to CRBN modulates the targeting of substrate proteins for ubiquitination and proteasomal degradation.2,3,6-11 In preclinical studies, this mechanism has been shown to underlie the anti-proliferative and immunomodulatory activities of these agents in malignancies including multiple myeloma, lymphoma, and del(5q) myelodysplastic syndromes.2,3,6-10 Binding of lenalidomide to CRBN has been shown to have tumoricidal effects in non-Hodgkin lymphoma and multiple myeloma through inhibition of expression of oncogenes, such as IRF4.9,12,13 In del(5q) myelodysplastic syndromes, lenalidomide binding with the CRL4CRBN complex has been shown to induce ubiquitination of casein kinase 1A1 (CK1α), resulting in its degredation.7 In multiple myeloma, pomalidomide exhibits tumorcidal, immunomodulatory, and anti-stromal support activities through binding the CRL4CRBN complex.14 Binding to CRBN and the associated modulation of ubiquitination of proteins, as demonstrated in vitro, provide a molecular basis for the pharmacological activity of these immunomodulatory agents.

CRBN, cereblon; Cul4, cullin 4; DDB1, DNA damage-binding protein 1; immunomodulatory agent; Roc1, regulator of cullins 1.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

  1. Ito T, et al. Science. 2010;327:1345-1350.
  2. Lopez-Girona A, et al. Leukemia. 2012;26:2326-2335.
  3. Gandhi AK, et al. Br J Haematol. 2014;164:811-821.
  4. http://www.t1dbase.org/page/Overview/display/gene_id/297498.
  5. http://www.immgen.org/databrowser/index.html. Search term: CRBN.
  6. Xu Y, et al. Blood. 2009;114:338-345.
  7. Krönke J, et al. Science. 2014;343:301-305.
  8. Lu G, et al. Science. 2014;343:305-309.
  9. Zhang LH, et al. Br J Haematol. 2013;160:487-502.
  10. Fink EC, et al. Blood. 2014;124 [abstract 4].
  11. Hollenbach P, et al. Blood. 2014;124 [abstract 3606].
  12. Yang T, et al. Cancer Cell. 2012;21:727-737.
  13. Shaffer AL, et al. Clin Cancer Res. 2009;15:2954-2961.
  14. Quach H, et al. Leukemia. 2010;24:22-32.