Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs
| Autor: | Takumi Ito, Hiroshi Handa |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug medicine.medical_specialty Ubiquitin-Protein Ligases media_common.quotation_subject Antineoplastic Agents Pharmacology Substrate Specificity 03 medical and health sciences Ubiquitin Internal medicine medicine Humans Immunologic Factors Molecular Targeted Therapy Adaptor Proteins Signal Transducing media_common Hematology biology Cereblon Ubiquitin ligase Thalidomide 030104 developmental biology Mechanism of action Cancer cell biology.protein medicine.symptom Peptide Hydrolases medicine.drug |
| Zdroj: | International Journal of Hematology. 104:293-299 |
| ISSN: | 1865-3774 0925-5710 |
| Popis: | Thalidomide was first developed as a sedative around 60 years ago, but exhibited teratogenicity, leading to serious defects such as limb deformities. Nevertheless, thalidomide is now recognized as a therapeutic drug for the treatment of Hansen's disease and myeloma. Immunomodulatory drugs (IMiDs), a new class of anti-cancer drug derived from thalidomide, have also been developed and exert potent anti-cancer effects. Although the molecular mechanism of thalidomide and IMiDs remained unclear for a long time, cereblon, a substrate receptor of the CRL4 E3 ubiquitin ligase was identified as a primary direct target by a new affinity technique. A growing body of evidence suggests that the effect of IMiDs on myeloma and other cancer cells is mediated by CRBN. Each IMiD binds to CRBN and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins such as Ikaros and Aiolos. Here we give an overview of the current understanding of mechanism of action of IMiDs via CRBN and prospects for the development of new drugs that degrade protein of interest. |
| Databáze: | OpenAIRE |
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