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

The novel mechanism of lenalidomide activity.

Author information

1
Brigham and Women's Hospital, Division of Hematology, Boston, MA.

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.

PMID:
26438514
PMCID:
PMC4653765
DOI:
10.1182/blood-2015-07-567958
[Indexed for MEDLINE]
Free PMC Article

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