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. CPD 1 retains potent and selective HER2 inhibitory activity while exhibiting additional ferroptosis-associated activity and functional P-glycoprotein-modulatory activity in vitro. 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 btucatinib. Its mechanism involves effective inhibition of the HER2/PI3K/AKT pathway alongside induction of lipid peroxidation and glutathione depletion. In vivo evaluations demonstrated dose-dependent inhibition of subcutaneous tumour growth and a significant reduction in brain metastatic lesion burden at the experimental endpoint. Pharmacokinetic studies demonstrated measurable total brain exposure of CPD 1, with a total brain-to-plasma partition coefficient (Kp, brain) of 0.52; unbound brain exposure was not determined. Furthermore, preliminary toxicological assessments did not show overt toxicity at the tested doses. In summary, CPD 1 combines potent HER2 inhibition with ferroptosis-associated activity demonstrated in vitro and measurable brain exposure in preclinical pharmacokinetic studies. These properties suggest its potential to address challenges associated with HER2-positive breast cancer and CNS metastases, warranting further investigation.