Blood Spotlight The novel mechanism of lenalidomide activity

Lenalidomide is a highly effective treatment for multiple myeloma, other B-cell neoplasms including mantle cell lymphoma and chronic lymphocytic leukemia, and myelodysplastic syndrome (MDS) with del(5q). Lenalidomide is a derivative of thalidomide, infamous for its teratogenicity following use as an anti-emetic in pregnant women. Thalidomide, lenalidomide, and another derivative, pomalidomide (Figure 1), increase IL-2production inT lymphocytes anddecrease pro-inflammatory cytokines, leading to their designation as immunomodulatory drugs (IMiDs). Despite their widespread clinical use, these drugs were developed before elucidation of themolecular basis of their activity. Recent studies have revealed that thalidomide, lenalidomide, and pomalidomide share a novel pharmacologic mechanism of action (Figure 2). The drugs bind to an E3 ubiquitin ligase complex and modulate its substrate specificity, resulting in the proteasomal degradation of specific disease-related proteins. These are the first approved drugs to target an E3 ubiquitin ligase, demonstrating the potential for the development of new therapies that modulate ubiquitination. In lymphocytes, these drugs induce rapid and effective degradation of Ikaros (IKZF1) and Aiolos (IKZF3), 2 zinc finger transcription factors that would generally be considered “undruggable.” Thalidomide, lenalidomide, and pomalidomide may represent the first in a new class of pharmacologic agents that alter the abundance of specific proteins by targeting ubiquitin ligase activity. Here, we review recent advances in the understanding of this mechanism as well as questions left unanswered.