Brigatinib-based targeted drug conjugates afford selective and potent anti-tumor efficacy in the treatment of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, as existing therapies lack sufficient tumor selectivity and offer dose-limiting systemic toxicity. Herein report is the design, synthesis, and biological evaluation of five novel EGFR-targeted drug conjugates (TDCs) upon our TDC strategy, which employs Brigatinib as the targeting moiety linked to various cytotoxic payloads. Molecular docking-guided conjugation maintained EGFR binding affinity across all TDCs (IC50 = 0.14-0.24 nM), and the representative compound BG2 exhibited potent antiproliferative activity against PANC-1 cells (IC50 = 0.68 μM) with a high selectivity index relative to normal cells. Further investigations revealed a diverse antitumor profile, mainly including inhibition of the EGFR/AKT pathway and induction of DNA double-strand breaks. In a PANC-1 xenograft model, BG2 achieved 67.79% tumor growth inhibition while preserving organ histology and maintaining stable body weight. These findings highlight the potential of the Brigatinib-based TDC platform as a precision therapeutic strategy for PDAC.