The novel mechanism of lenalidomide activity

Abstract

Lenalidomide acts by a novel drug mechanism—modulation of the substrate specificity of the CRL4CRBN E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and IKZF3 by CRL4CRBN. Subsequent proteasomal degradation of these transcription factors kills multiple myeloma cells. In del(5q) myelodysplastic syndrome, lenalidomide induces the degradation of CK1α, which preferentially affects del(5q) cells because they express this gene at haploinsufficient levels. In the future, modulation of ubiquitin ligase function may enable us to target previously “undruggable” proteins.

Primary plasma cell leukemia: A case report and review of the literature

“…Synergism between IMiDs and proteasome inhibitors can be utilized in treatment of patients refractory to lenalidomide. This synergism can be explained by a novel mechanism of action of lenalidomide which involves increased protein ubiquitination …”

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

“…Tafamidis binds to the dimer interface and stabilizes transthyretin dimers, which are destabilized in this disease . Other examples of drugs proposed to proceed through this mechanism include lenalidomide; a thalidomide analogue approved to treat myelodisplasic syndromes . On the flip side, downregulation can also be induced.…”

Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications

“…The effects of lenalidomide in 5q− MDS is explained by lenalidomide acting though karyotype‐dependent pathways mediated by haplodeficient genes (Fig. ) …”

“…In a seminal recent paper, Kronke et al identified a completely novel mechanism for the activity of lenalidomide in 5q− MDS . Lenalidomide binds to the E3 ubiquitin ligase complex and modulates its binding to disease‐specific substrates resulting in subsequent ubiquitination and proteasomal degradation of these substrates.…”

“…Several clinical trials have demonstrated a substantial clinical benefit of lenalidomide in MDS with 5q− as well as a less pronounced effect in MDS without 5q− . The mechanism of action of lenalidomide is complex and remained incompletely understood until recently . This review focuses on new insights into the mechanism of action of lenalidomide in MDS as well as the recent clinical evidence of lenalidomide use in MDS with and without 5q−.…”