Molecular mechanisms of thalidomide and its derivatives

Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanis...

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Bibliographic Details
Published inProceedings of the Japan Academy, Series B Vol. 96; no. 6; pp. 189 - 203
Main Authors ITO, Takumi, HANDA, Hiroshi
Format Journal Article
LanguageEnglish
Published Japan The Japan Academy 11.06.2020
Subjects
Animals
Beads
cereblon
Chimeras
Cullin
Deoxyribonucleic acid
Derivatives
DNA
DNA repair
Drug Repositioning
Drugs
Enzymes
Erythema
FDA approval
Hematological diseases
Humans
immunomodulatory imide drugs (IMiDs)
lenalidomide
Ligands
Lymphoma
Molecular modelling
Molecular Targeted Therapy
Multiple myeloma
Pharmaceutical industry
Proteins
Proteolysis
proteolysis targeting chimeras (PROTACs)
Researchers
Review
Substrates
Teratogenicity
Thalidomide
Thalidomide - adverse effects
Thalidomide - chemistry
Thalidomide - pharmacology
Ubiquitin
Ubiquitin-protein ligase
United States > US
Japan
immunomodulatory imide drugs (IMiDs)
cereblon
lenalidomide
thalidomide
ubiquitin
proteolysis targeting chimeras (PROTACs)
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Summary:Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanisms of thalidomide and its derivatives remained poorly understood until recently, we identified cereblon (CRBN), a primary direct target of thalidomide, using ferrite glycidyl methacrylate (FG) beads. CRBN is a ligand-dependent substrate receptor of the E3 ubiquitin ligase complex cullin-RING ligase 4 (CRL4CRBN). When a ligand such as thalidomide binds to CRBN, it recognizes various ‘neosubstrates’ depending on the shape of the ligand. CRL4CRBN binds many neosubstrates in the presence of various ligands. CRBN has been utilized in a novel protein knockdown technology named proteolysis targeting chimeras (PROTACs). Heterobifunctional molecules such as dBET1 are being developed to specifically degrade proteins of interest. Herein, we review recent advances in CRBN research.
Bibliography:Edited by Shigekazu NAGATA, M.J.A.
ISSN:0386-2208
1349-2896
DOI:10.2183/pjab.96.016