Research and Development of a Multi-Target HER2 Inhibitor (CPD 1) and Its Mechanism and Application in Combating HER2-Positive Breast Cancer

HER2-positive breast cancer, particularly in patients with central nervous system metastasis, presents significant clinical challenges due to limited treatment options and extremely poor prognosis. This paper reports the rational design, synthesis, and systematic evaluation of a novel multi-target HER2 inhibitor, CPD 1. Employing a ‘skeletal leap-pharmacophore retention-multi-mechanism synergy’ design strategy, CPD 1 retains highly selective HER2 inhibitory activity while incorporating a flavonoid derivative moiety to synergistically induce ferroptosis and inhibit P-glycoprotein efflux. In vitro studies demonstrate potent antiproliferative activity of CPD 1 against a panel of HER2-positive breast cancer cells (including PIK3CA mutant variants), exhibiting significantly superior IC₅₀ values compared to trastuzumab. Its mechanism involves effective inhibition of the HER2/PI3K/AKT pathway alongside induction of lipid peroxidation and glutathione depletion. In vivo pharmacodynamic evaluations in subcutaneous xenograft and brain metastasis models confirmed that CPD 1 dose-dependently inhibited tumour growth, significantly delayed the formation of brain metastases, and reduced the number of metastatic lesions, demonstrating superior efficacy to the positive control drug Tucatinib. Pharmacokinetic studies revealed CPD 1's exceptional blood-brain barrier penetration (brain tissue/plasma concentration ratio > 0.5), underpinning its potent anti-CNS metastatic activity. Furthermore, preliminary toxicological assessments indicate CPD 1 possesses a broad safety margin. In summary, CPD 1 emerges as a novel candidate drug integrating potent HER2 inhibition, ferroptosis induction, and favourable brain exposure. It offers a highly promising solution for overcoming the clinical challenge of HER2-positive breast cancer and its CNS metastases.