A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

Mary E. Matyskiela, Gang Lu (), Takumi Ito, Barbra Pagarigan, Chin-Chun Lu, Karen Miller, Wei Fang, Nai-Yu Wang, Derek Nguyen, Jack Houston, Gilles Carmel, Tam Tran, Mariko Riley, Lyn’Al Nosaka, Gabriel C. Lander, Svetlana Gaidarova, Shuichan Xu, Alexander L. Ruchelman, Hiroshi Handa, James Carmichael, Thomas O. Daniel, Brian E. Cathers, Antonia Lopez-Girona and Philip P. Chamberlain ()
Additional contact information
Mary E. Matyskiela: Celgene Corporation
Gang Lu: Celgene Corporation
Takumi Ito: Tokyo Medical University
Barbra Pagarigan: Celgene Corporation
Chin-Chun Lu: Celgene Corporation
Karen Miller: Celgene Corporation
Wei Fang: Celgene Corporation
Nai-Yu Wang: Celgene Corporation
Derek Nguyen: Celgene Corporation
Jack Houston: Celgene Corporation
Gilles Carmel: Celgene Corporation
Tam Tran: Celgene Corporation
Mariko Riley: Celgene Corporation
Lyn’Al Nosaka: The Scripps Research Institute
Gabriel C. Lander: The Scripps Research Institute
Svetlana Gaidarova: Celgene Corporation
Shuichan Xu: Celgene Corporation
Alexander L. Ruchelman: Celgene Corporation
Hiroshi Handa: Tokyo Medical University
James Carmichael: Celgene Corporation
Thomas O. Daniel: Celgene Corporation
Brian E. Cathers: Celgene Corporation
Antonia Lopez-Girona: Celgene Corporation
Philip P. Chamberlain: Celgene Corporation

Nature, 2016, vol. 535, issue 7611, 252-257

Abstract: Abstract Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBN 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.

Date: 2016
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DOI: 10.1038/nature18611

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