Lenalidomide

Brand Name: Revlimid

Lenalidomide is an immunomodulatory imide drug (IMiD) used to treat multiple myeloma, myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma.1

How Does Lenalidomide Work?

protein degradation and recycling

Protein degradation is an important process that enables cells to eliminate abnormal or unnecessary proteins, recycle protein components, and adapt to changing cellular conditions.

Ubiquitin ligase attaches ubiquitin to a target protein recruited by cereblon

Ubiquitination is one of the pathways cells utilize to degrade proteins. In this pathway, a protein called ubiquitin ligase tags a target protein with ubiquitin, which serves as a signal for protein degradation.2 Other proteins, such as cereblon, recruit specific target proteins, ensuring that only proteins that need to be degraded are marked with ubiquitin.3

Cereblon, with lenalidomide bound, recruits Ikaros

Lenalidomide is a drug that binds to cereblon at its target protein-binding site. This alters the target protein specificity of cereblon towards another family of proteins called Ikaros. As a result, Ikaros proteins are marked with ubiquitin and degraded.4

Lenalidomide treatment leads to Ikaros degradation, ultimately resulting in cancer cell death

Ikaros is a protein essential for the development of B cells, a type of immune cell.5 Some cancers that originate from B cells, such as multiple myeloma, rely on Ikaros to drive their uncontrolled growth.4 Therefore, lenalidomide, by leading to Ikaros degradation, halts their growth and ultimately leads to cancer cell death.

References

1. REVLIMID - Label. U.S. Food and Drug Administration (2023).

2. Hershko, A. & Ciechanover, A. The ubiquitin system. Annual Review of Biochemistry 67, 425-479 (1998).

3. Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49-53 (2014).

4. Krönke, J. et al. Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells. Science 343(6168), 301-305 (2013).

5. Schwickert, T. A. et al.Stage-specific control of early B cell development by the transcription factor Ikaros. Nature Immunology 15, 283-293 (2014).