Construction of A Synthetic Methodology-Based Library and Its Application in Identifying the First GIT/PIX Protein–Protein Interaction Inhibitor

Abstract The rapid and efficient hit discovery is highly dependent on the development of multifarious chemical libraries. 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 compounds screening has not been systematically evaluated. In the present work, we have established a synthetic methodology-based compound library (SMBL), integrated of compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We further screened the library and identified the first 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 retarded gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered “undruggable” that were hard to be targeted, the successful identification of the inhibitor illustrated the structural diversity and specificity of SMBL, demonstrating its potential to be utilized as compound source for targeting some challenging targets.