title: A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase.
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.
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Matyskiela
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Barbra
authors.initials: B
authors.lastname: Pagarigan
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Chin-Chun
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Miller
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Nai-Yu
authors.initials: NY
authors.lastname: Wang
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Houston
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Gilles
authors.initials: G
authors.lastname: Carmel
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Tam
authors.initials: T
authors.lastname: Tran
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Riley
authors.affiliation: The Scripps Research Institute, San Diego, California 92121, USA.
authors.forename: Lyn'Al
authors.initials: L
authors.lastname: Nosaka
authors.affiliation: The Scripps Research Institute, San Diego, California 92121, USA.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Lander
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gaidarova
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Shuichan
authors.initials: S
authors.lastname: Xu
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Ruchelman
authors.affiliation: Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cathers
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.affiliation: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, USA.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Chamberlain
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D059748:Proteolysis / Q000187:drug effects; D013379:Substrate Specificity; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C000609735:CC-885; C502543:CRBN protein, human; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D010454:Peptide Termination Factors; D010671:Phenylurea Compounds; C087971:peptide-chain-release factor 3; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases