The novel mechanism of lenalidomide activity

Abstract

Lenalidomide acts by a novel drug mechanism-modulation of the substrate specificity of the CRL4(CRBN) E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and IKZF3 by CRL4(CRBN). 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.

Figure 1

Chemical structures of IMiD compounds. (A) Chemical structures of thalidomide, lenalidomide, and pomalidomide, with pthaloyl and glutarimide rings indicated. (B) Chemical structure of CC-122.

Figure 2

Mechanism of lenalidomide in multiple myeloma and del(5q) MDS. Lenalidomide binds to CRBN, the substrate adaptor of the CRL4^CRBN E3 ubiquitin ligase. Lenalidomide induces the recruitment of specific substrates to CRL4^CRBN and their ubiquitination by this ligase. In multiple myeloma, the ubiquitination and subsequent proteasomal degradation of two B-cell transcription factors, IKZF1 and IKZF3, kills multiple myeloma cells. In del(5q) MDS, the ubiquitination and degradation of casein kinase 1A1 causes the death of del(5q) cells, because they express this protein at haploinsufficient levels. Yellow hexagons represent ubiquitin molecules.