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Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor

Author

Listed:
  • Jing Gu

    (Third Military Medical University)

  • Rui-Kun Peng

    (Third Military Medical University)

  • Chun-Ling Guo

    (Third Military Medical University)

  • Meng Zhang

    (Shanghai Jiao Tong University)

  • Jie Yang

    (Third Military Medical University)

  • Xiao Yan

    (Third Military Medical University)

  • Qian Zhou

    (Third Military Medical University)

  • Hongwei Li

    (Third Military Medical University)

  • Na Wang

    (Third Military Medical University)

  • Jinwei Zhu

    (Shanghai Jiao Tong University)

  • Qin Ouyang

    (Third Military Medical University)

Abstract

In recent years, the flourishing of synthetic methodology studies has provided concise access to numerous molecules with new chemical space. These compounds form a large library with unique scaffolds, but their application in hit discovery is not systematically evaluated. In this work, we establish a synthetic methodology-based compound library (SMBL), integrated with compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We screen the library and identify small-molecule inhibitors to interrupt the protein–protein interaction (PPI) of GIT1/β-Pix complex, an unrevealed target involved in gastric cancer metastasis. The inhibitor 14-5-18 with a spiro[bicyclo[2.2.1]heptane-2,3’-indolin]−2’-one scaffold, considerably retards gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered undruggable as they are hard to target, the successful application illustrates the structural specificity of SMBL, demonstrating its potential to be utilized as compound source for more challenging targets.

Suggested Citation

  • Jing Gu & Rui-Kun Peng & Chun-Ling Guo & Meng Zhang & Jie Yang & Xiao Yan & Qian Zhou & Hongwei Li & Na Wang & Jinwei Zhu & Qin Ouyang, 2022. "Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34598-7
    DOI: 10.1038/s41467-022-34598-7
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