Abstract
Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Motifs
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Binding Sites
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Crystallography, X-Ray
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism
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Humans
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Ikaros Transcription Factor / chemistry
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Ikaros Transcription Factor / metabolism
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Models, Molecular
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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Peptide Hydrolases / chemistry
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Peptide Hydrolases / metabolism*
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Peptide Termination Factors / chemistry
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Peptide Termination Factors / deficiency
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Peptide Termination Factors / metabolism*
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology*
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Protein Binding
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Proteolysis / drug effects
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Substrate Specificity
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Thalidomide / analogs & derivatives*
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Thalidomide / chemistry
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Thalidomide / pharmacology
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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CC-885
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CRBN protein, human
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DDB1 protein, human
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DNA-Binding Proteins
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Multiprotein Complexes
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Peptide Termination Factors
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Phenylurea Compounds
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peptide-chain-release factor 3
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Ikaros Transcription Factor
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Thalidomide
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Ubiquitin-Protein Ligases
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Peptide Hydrolases