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A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Nos, 2016. "A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 535(7611), pages 252-257, July.
  • Handle: RePEc:nat:nature:v:535:y:2016:i:7611:d:10.1038_nature18611
    DOI: 10.1038/nature18611
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    Cited by:

    1. Jian Ma & Lei Li & Bohan Ma & Tianjie Liu & Zixi Wang & Qi Ye & Yunhua Peng & Bin Wang & Yule Chen & Shan Xu & Ke Wang & Fabin Dang & Xinyang Wang & Zixuan Zeng & Yanlin Jian & Zhihua Ren & Yizeng Fan, 2024. "MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Gisele Nishiguchi & Lauren G. Mascibroda & Sarah M. Young & Elizabeth A. Caine & Sherif Abdelhamed & Jeffrey J. Kooijman & Darcie J. Miller & Sourav Das & Kevin McGowan & Anand Mayasundari & Zhe Shi &, 2024. "Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Alena Kroupova & Valentina A. Spiteri & Zoe J. Rutter & Hirotake Furihata & Darren Darren & Sarath Ramachandran & Sohini Chakraborti & Kevin Haubrich & Julie Pethe & Denzel Gonzales & Andre J. Wijaya , 2024. "Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Zemin Zhang & Yuanqing Li & Jie Yang & Jiacheng Li & Xiongqiang Lin & Ting Liu & Shiling Yang & Jin Lin & Shengyu Xue & Jiamin Yu & Cailing Tang & Ziteng Li & Liping Liu & Zhengzheng Ye & Yanan Deng &, 2024. "Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Satoshi Yamanaka & Hirotake Furihata & Yuta Yanagihara & Akihito Taya & Takato Nagasaka & Mai Usui & Koya Nagaoka & Yuki Shoya & Kohei Nishino & Shuhei Yoshida & Hidetaka Kosako & Masaru Tanokura & Ta, 2023. "Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Zefeng Wang & Shabnam Shaabani & Xiang Gao & Yuen Lam Dora Ng & Valeriia Sapozhnikova & Philipp Mertins & Jan Krönke & Alexander Dömling, 2023. "Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Shiyun Cao & Shoukai Kang & Haibin Mao & Jiayu Yao & Liangcai Gu & Ning Zheng, 2022. "Defining molecular glues with a dual-nanobody cannabidiol sensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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