Identification of YES1 Inhibitors From Approved Drugs Using a Multimodal Deep Learning Framework

While anti-human epidermal growth factor receptor 2 (HER2) drugs, including trastuzumab improve the prognosis of patients with HER2-positive cancers, acquired resistance by cancer cells remains a significant clinical challenge. We had previously reported that YES1 is overexpressed in trastuzumab-resistant breast and lung cancer cells, and that its inhibition restores trastuzumab sensitivity. However, no approved drug specifically targets YES1. In this study, as a drug repositioning approach aimed at rapid clinical application, we constructed a machine learning model capable of learning the interactions between compounds and target proteins and conducted a screening of approved drugs. The strategy identified chlorpromazine and raloxifene as hit compounds. In vitro validation demonstrated that they effectively inhibited YES1 activation at 15 μM after 48 h. The findings suggested that the identified approved drugs might represent promising therapeutic options for overcoming anti-HER2 drug resistance.