新型SHP2抑制剂BGC1201抗非小细胞肺癌、胰腺肿瘤和食道肿瘤药效学研究

Objective Compound BGC1201 is a novel SHP2 inhibitor developed through a fragment-based drug design (FBDD) strategy, with optimized moieties responsible for hERG inhibition in allosteric SHP2 inhibitors. Methods This study investigates the inhibitory activity of BGC1201 against SHP2-WT phosphatase and p-ERK, its antiproliferative effects on 14 tumor cell lines (including MIA PaCa-2), and its antitumor efficacy in nude mouse xenograft models of human lung cancer (NCI-H358), pancreatic cancer (MIA PaCa-2), and esophageal cancer (KYSE-520). Results BGC1201 exhibits potent inhibition against SHP2-WT phosphatase (IC50 = 2.47 nM). At the cellular level, BGC1201 suppresses p-ERK expression in NCI-H358 cells with an IC50 of 17.3 nM. It inhibits proliferation in 12 out of 14 tested cell lines, showing significant effects on MIA PaCa-2, HCT-116, and NCI-H358 cells. In three xenograft models, BGC1201 (3 mg kg?1) achieves tumor growth inhibition rates of 62%, 54%, and 92%, comparable to the positive control TNO155 (30 mg kg?1), while outperforming TNO155 at equivalent doses. Western blot analysis reveals that BGC1201 exerts antitumor activity by downregulating p-ERK expression in tumor tissues. Conclusion BGC1201 demonstrates remarkable antitumor efficacy both in vitro and in vivo, laying a foundation for further clinical development.