Design, Synthesis and Evaluation of Novel Cyclopropanesulfonamide Derivatives for the Treatment of EGFRC797S Mutation in Non-Small Cell Lung Cancer.

Abstract

Background: The 797S mutation in EGFR disrupts the covalent binding of third-generation inhibitors, causing drug resistance. Currently, no clinically drug fully overcomes this resistance.

Methods: We designed and synthesised a novel EGFR C797S-targeted inhibitor-5d by introducing structures such as cyclopropyl and sulfonamide with Brigatinib as the lead compound; we identified the target of action by ELISA and molecular docking, and tested its anti-tumor activity and safety in vivo and vitro, as well as its effects on cell cycle, apoptosis and DNA damage.

Results: It was found that there were 10 new small-molecule inhibitors and compound 5d was identified as highly selective with low toxicity. WB confirmed 5d's inhibition of EGFR and m-TOR pathways. Mechanistic studies revealed 5d induced cell cycle arrest in G2/M phase caused DNA damage and cell apoptosis, increasing apoptotic protein cleaved caspase-3 levels. It also inhibited growth in PC9 cells with an EGFR^del19 mutation. Importantly, 5d also demonstrated superior anti-tumor activity in vivo and was superior to the positive control Brigatinib.

Conclusion: We concluded that cyclopropylsulfonamide 5d derivatives induce cell cycle arrest, apoptosis, and DNA damage by regulating tumor-related genes, thereby inhibiting the proliferation of C797S mutated lung cancer cells.