Design, Synthesis, and Anticancer Activity Evaluation of the New SHP2 Degraders

Abstract

SHP2 is closely related to the occurrence of cancer and has been identified as a potential anti-cancer target. In this study, we applied PROTAC technology to design and synthesize four PROTAC molecules targeting SHP2. The CCK8 experiment displayed that these compounds had strong anti-cancer effects. Among them, compound 5b had the strongest activity, with an IC₅₀ value of 2.76 µm for non-small cell lung cancer cells NCI-H1975, slightly higher than the positive control IACS-13909, but with a 3-fold decrease in toxicity. It was worth noting that compound 5b had a synergistic effect with the EGFR inhibitor osimertinib against NCI-H1975 cells. Research displayed that compound 5b could effectively degrade SHP2. Molecular docking revealed that compound 5b could effectively dock to the SHP2 protein. Further experiments displayed that compound 5b could effectively downregulate the phosphorylation levels of Erk and Akt. Flow cytometry analysis displayed that compound 5b could induce apoptosis in NCI-H1975 cells. This study provides new insights for the development of SHP2 degraders.