Abstract 3056: Structural optimization of lapatinib analogs for overcoming CNS metastases in breast cancer

Abstract Due to its role in aggressive disease progression and poor clinical outcomes, HER-2 kinase was considered a vital target in breast cancer (BC). Central nervous system (CNS) metastases represent a significant challenge in HER2+ BC, as they are often refractory to existing therapies such as lapatinib. Our previous work focused on the structural optimization of lapatinib analogs to enhance potency, selectivity, and pharmacokinetics. The HER2-selective derivatives were synthesized and characterized, with nanomolar IC50 values range of [5.4-12 nM], more the reference drug lapatinib (IC50: 95.5 nM). Compound 17d demonstrated outstanding HER2 selectivity and minimal off-target kinase activation. Broad-spectrum activity was observed (GI50: 1.43-2.09 µM), with a strong preference for HER2+ BC cells over HER2− cells, achieving up to 20-fold selectivity in antiproliferative assays. Compound 17d emerges as a promising candidate with the potential to overcome the limitations of current HER2 therapies. Its potent HER2-selective inhibition, robust in vivo efficacy, and favorable pharmacokinetic profile highlight its therapeutic potential for HER2+ breast cancer. Our current study mainly focuses on the structural optimization of our lead compound to be more BBB penetrable to overcome the HER-2 CNS Metastatic cancers by applying in-silico, in-vitro, and in-vivo models. Citation Format: Mostafa Mohammed Ahmed Aref, Eneye D. Ajayi, Md A. Emran Hossain, Rokaia S. Abdullah, Hamed I. Ali. Structural optimization of lapatinib analogs for overcoming CNS metastases in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3056.