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

Jing Gu, Rui-Kun Peng, Chun-Ling Guo, Meng Zhang, Jie Yang, Xiao Yan, Qian Zhou, Hongwei Li, Na Wang, Jinwei Zhu () and Qin Ouyang ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34598-7

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