Discovery of isoquinoline-tethered quinazoline derivatives with enhanced HER2 inhibition over EGFR.

ABSTRACT: Human epidermal growth factor receptor 2 (HER2) is a critical therapeutic target for HER2-positive or HER2-dependent cancers. While several HER2 kinase inhibitors have been identified, achieving high selectivity for HER2 over EGFR remains a significant challenge. In this study, we aimed to develop HER2-selective inhibitors with enhanced cellular activity. To improve the limited cellular activity of derivatives with a quinoline moiety against HER2, we synthesized a novel series of derivatives by bioisosteric replacement. These derivatives demonstrated significantly improved selectivity for HER2 over EGFR, with a 7- to 12-fold enhancement compared to lapatinib in kinase assays. Furthermore, they exhibited enhanced cellular activity, leading to improved anti-proliferative effects against HER2

SUBMITTER: Lee JW 

PROVIDER: S-EPMC11886616 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature