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Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex

Author

Listed:
  • Zemin Zhang

    (Fujian Medical University)

  • Yuanqing Li

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Jie Yang

    (Fujian Normal University)

  • Jiacheng Li

    (Chinese Academy of Sciences)

  • Xiongqiang Lin

    (Fujian Medical University)

  • Ting Liu

    (Fujian Medical University)

  • Shiling Yang

    (Fujian Normal University)

  • Jin Lin

    (Fujian Medical University)

  • Shengyu Xue

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Jiamin Yu

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Cailing Tang

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Ziteng Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Liping Liu

    (Chinese Academy of Sciences)

  • Zhengzheng Ye

    (University of Chinese Academy of Sciences)

  • Yanan Deng

    (University of Chinese Academy of Sciences)

  • Zhihai Li

    (University of Chinese Academy of Sciences)

  • Kaixian Chen

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hong Ding

    (Chinese Academy of Sciences
    Guizhou Medical University)

  • Cheng Luo

    (Fujian Medical University
    Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hua Lin

    (Chinese Academy of Sciences
    Fujian Normal University
    Chinese Academy of Sciences)

Abstract

Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50642-0
    DOI: 10.1038/s41467-024-50642-0
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    References listed on IDEAS

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    1. 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.
    2. Qiangfeng Cliff Zhang & Donald Petrey & Lei Deng & Li Qiang & Yu Shi & Chan Aye Thu & Brygida Bisikirska & Celine Lefebvre & Domenico Accili & Tony Hunter & Tom Maniatis & Andrea Califano & Barry Honi, 2012. "Structure-based prediction of protein–protein interactions on a genome-wide scale," Nature, Nature, vol. 490(7421), pages 556-560, October.
    3. Youyi Zhang & Fei Ye & Tongtong Zhang & Shiyun Lv & Liping Zhou & Daohai Du & He Lin & Fei Guo & Cheng Luo & Shujia Zhu, 2021. "Author Correction: Structural basis of ketamine action on human NMDA receptors," Nature, Nature, vol. 598(7882), pages 3-3, October.
    4. Youyi Zhang & Fei Ye & Tongtong Zhang & Shiyun Lv & Liping Zhou & Daohai Du & He Lin & Fei Guo & Cheng Luo & Shujia Zhu, 2021. "Structural basis of ketamine action on human NMDA receptors," Nature, Nature, vol. 596(7871), pages 301-305, August.
    5. Eric S. Fischer & Kerstin Böhm & John R. Lydeard & Haidi Yang & Michael B. Stadler & Simone Cavadini & Jane Nagel & Fabrizio Serluca & Vincent Acker & Gondichatnahalli M. Lingaraju & Ritesh B. Tichkul, 2014. "Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide," Nature, Nature, vol. 512(7512), pages 49-53, August.
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