Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond

Curr Opin Cell Biol. 2015 Dec;37:61-7. doi: 10.1016/j.ceb.2015.10.004. Epub 2015 Nov 11.

Abstract

Lenalidomide and its related 'analogues' modulate the substrate specificity of the CRL4(CRBN) E3 ubiquitin ligase complex. Polyubiquitination and subsequent proteasomal degradation of IKZF1 and IKZF3 in multiple myeloma and CK1α in del(5q) MDS has recently been linked to therapeutic efficacy of this class of compounds. Harnessing ubiquitin ligase substrate specificity, may in time facilitate the degradation of other 'undruggable' proteins and allow for separation of detrimental side effects of IMiD compounds from those associated with therapeutic efficacy.

Publication types

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

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Humans
  • Lenalidomide
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / metabolism
  • Substrate Specificity
  • Thalidomide / analogs & derivatives*
  • Thalidomide / therapeutic use
  • Transcription, Genetic
  • Ubiquitination

Substances

  • Angiogenesis Inhibitors
  • Thalidomide
  • Lenalidomide