The molecular mechanism of thalidomide analogs in hematologic malignancies.

Abstract

Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-α and increase interleukin-2 (IL-2) and interferon-γ release from T cells. The underlying molecular mechanisms for these pleiotropic effects remained obscure until the identification of the cereblon (CRBN) E3 ubiquitin ligase as the primary target of thalidomide and its analogs in 2010. Binding of thalidomide or lenalidomide increases the affinity of CRBN to the transcription factors IKZF1 and IKZF3 and casein kinase 1α (CK1α). Ubiquitination and degradation of these neo-substrates results in IL-2 release and growth arrest of multiple myeloma and MDS cells. The discovery of this previously undescribed mechanism for an approved drug provides a proof-of-concept for the development of new therapeutics that exploit ubiquitin ligases for specific degradation of disease-associated proteins.

• Authors: Stefanie Lindner, Jan Krönke
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 94 Issue 12 Pg. 1327-1334 (12 2016) ISSN: 1432-1440 [Electronic] Germany
• PMID: 27492707 (Publication Type: Journal Article, Review)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• CRBN protein, human
• IKZF1 protein, human
• IKZF3 protein, human
• Interleukin-2
• Ikaros Transcription Factor
• Thalidomide
• pomalidomide
• Ubiquitin-Protein Ligases
• Casein Kinase I
• Peptide Hydrolases
• Lenalidomide

Topics

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents (therapeutic use)
• Casein Kinase I (genetics, immunology)
• Gene Expression Regulation, Neoplastic
• Humans
• Ikaros Transcription Factor (genetics, immunology)
• Interleukin-2 (biosynthesis, metabolism)
• Lenalidomide
• Multiple Myeloma (drug therapy, genetics, immunology, pathology)
• Myelodysplastic Syndromes (drug therapy, genetics, immunology, pathology)
• Peptide Hydrolases (genetics, immunology)
• Protein Binding
• Proteolysis (drug effects)
• Signal Transduction
• Thalidomide (analogs & derivatives, therapeutic use)
• Ubiquitin-Protein Ligases
• Ubiquitination (drug effects)