A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

被引:428
作者
Matyskiela, Mary E. [1 ]
Lu, Gang [1 ]
Ito, Takumi [2 ]
Pagarigan, Barbra [1 ]
Lu, Chin-Chun [1 ]
Miller, Karen [1 ]
Fang, Wei [1 ]
Wang, Nai-Yu [1 ]
Nguyen, Derek [1 ]
Houston, Jack [1 ]
Carmel, Gilles [1 ]
Tran, Tam [1 ]
Riley, Mariko [1 ]
Nosaka, Lyn'Al [3 ]
Lander, Gabriel C. [3 ]
Gaidarova, Svetlana [1 ]
Xu, Shuichan [1 ]
Ruchelman, Alexander L. [1 ]
Handa, Hiroshi [2 ]
Carmichael, James [1 ]
Daniel, Thomas O. [1 ]
Cathers, Brian E. [1 ]
Lopez-Girona, Antonia [1 ]
Chamberlain, Philip P. [1 ]
机构
[1] Celgene Corp, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA
[2] Tokyo Med Univ, Dept Nanoparticle Translat Res, Shinjuku Ku, Tokyo 1608402, Japan
[3] Scripps Res Inst, San Diego, CA 92121 USA
基金
美国国家卫生研究院;
关键词
LENALIDOMIDE; TARGET; DEGRADATION; PROTEINS; COMPLEX; IKAROS; POMALIDOMIDE; RECOGNITION; THALIDOMIDE; HYDROXYPROLINE;
D O I
10.1038/nature18611
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:252 / +
页数:24
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