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, Qin Ouyang

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Article number7176
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes

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