The novel mechanism of lenalidomide activity

Blood. 2015 Nov 19;126(21):2366-9. doi: 10.1182/blood-2015-07-567958. Epub 2015 Oct 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Ikaros Transcription Factor / genetics
  • Ikaros Transcription Factor / metabolism
  • Lenalidomide
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis / drug effects*
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacokinetics
  • Thalidomide / therapeutic use
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • IKZF1 protein, human
  • IKZF3 protein, human
  • Ikaros Transcription Factor
  • Thalidomide
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Lenalidomide