title: 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.
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, MA.
authors.forename: Emma C
authors.identifier: http://orcid.org/0000-0002-6589-8558
authors.initials: EC
authors.lastname: Fink
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, MA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000818:Animals; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000077269:Lenalidomide