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Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction

Author

Listed:
  • Kyle R. Simonetta

    (Nurix Therapeutics, Inc.)

  • Joshua Taygerly

    (Nurix Therapeutics, Inc.)

  • Kathleen Boyle

    (Nurix Therapeutics, Inc.)

  • Stephen E. Basham

    (Nurix Therapeutics, Inc.)

  • Chris Padovani

    (Nurix Therapeutics, Inc.
    University of California)

  • Yan Lou

    (Nurix Therapeutics, Inc.
    NiKang Therapeutics)

  • Thomas J. Cummins

    (Nurix Therapeutics, Inc.)

  • Stephanie L. Yung

    (Nurix Therapeutics, Inc.)

  • Szerenke Kiss Soly

    (Nurix Therapeutics, Inc.)

  • Frank Kayser

    (Nurix Therapeutics, Inc.
    BioArdis)

  • John Kuriyan

    (University of California)

  • Michael Rape

    (University of California)

  • Mario Cardozo

    (Nurix Therapeutics, Inc.)

  • Mark A. Gallop

    (Nurix Therapeutics, Inc.
    5AM Ventures)

  • Neil F. Bence

    (Nurix Therapeutics, Inc.)

  • Paul A. Barsanti

    (Nurix Therapeutics, Inc.
    5AM Ventures)

  • Anjanabha Saha

    (Nurix Therapeutics, Inc.
    5AM Ventures)

Abstract

Protein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCFβ-TrCP. These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of ‘molecular glue’ presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins.

Suggested Citation

  • Kyle R. Simonetta & Joshua Taygerly & Kathleen Boyle & Stephen E. Basham & Chris Padovani & Yan Lou & Thomas J. Cummins & Stephanie L. Yung & Szerenke Kiss Soly & Frank Kayser & John Kuriyan & Michael, 2019. "Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09358-9
    DOI: 10.1038/s41467-019-09358-9
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    Cited by:

    1. 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.
    2. Seref Gul & Yasemin Kubra Akyel & Zeynep Melis Gul & Safak Isin & Onur Ozcan & Tuba Korkmaz & Saba Selvi & Ibrahim Danis & Ozgecan Savlug Ipek & Fatih Aygenli & Ali Cihan Taskin & Büşra Aytül Akarlar , 2022. "Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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