Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger Cyclin K degradation

  1. Lu Lv
  2. Peihao Chen
  3. Longzhi Cao
  4. Yamei Li
  5. Zhi Zeng
  6. Yue Cui
  7. Qingcui Wu
  8. Jiaojiao Li
  9. Jian-Hua Wang
  10. Meng-Qiu Dong
  11. Xiangbing Qi  Is a corresponding author
  12. Ting Han  Is a corresponding author
  1. National Institute of Biological Sciences, China
  2. National Institute of Biological Sciemces, China

Abstract

Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Sequencing data have been deposited in GEO (GSE153700 and GSE153707).

The following data sets were generated

Article and author information

Author details

  1. Lu Lv

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    Lu Lv, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2075-8620
  2. Peihao Chen

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    Peihao Chen, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
  3. Longzhi Cao

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    Longzhi Cao, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
  4. Yamei Li

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    Yamei Li, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
  5. Zhi Zeng

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  6. Yue Cui

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  7. Qingcui Wu

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    Qingcui Wu, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
  8. Jiaojiao Li

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    Jiaojiao Li, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
  9. Jian-Hua Wang

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  10. Meng-Qiu Dong

    NIBS, National Institute of Biological Sciences, Beijing, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6094-1182
  11. Xiangbing Qi

    NIBS, National Institute of Biological Sciemces, Beijing, China
    For correspondence
    qixiangbing@nibs.ac.cn
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7139-5164
  12. Ting Han

    NIBS, National Institute of Biological Sciences, Beijing, China
    For correspondence
    hanting@nibs.ac.cn
    Competing interests
    Ting Han, A provisional patent application (PCT/CN2020/095482) has been filed for the application of HQ461 and related small molecules as molecular glues regulating CDK12-DDB1 interaction to degrade CCNK..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3168-8699

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wade Harper, Harvard Medical School, United States

Version history

  1. Received: June 13, 2020
  2. Accepted: August 14, 2020
  3. Accepted Manuscript published: August 17, 2020 (version 1)
  4. Version of Record published: September 1, 2020 (version 2)
  5. Version of Record updated: September 15, 2020 (version 3)

Copyright

© 2020, Lv et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lu Lv
  2. Peihao Chen
  3. Longzhi Cao
  4. Yamei Li
  5. Zhi Zeng
  6. Yue Cui
  7. Qingcui Wu
  8. Jiaojiao Li
  9. Jian-Hua Wang
  10. Meng-Qiu Dong
  11. Xiangbing Qi
  12. Ting Han
(2020)
Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger Cyclin K degradation
eLife 9:e59994.
https://doi.org/10.7554/eLife.59994

Share this article

https://doi.org/10.7554/eLife.59994

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