Design, Synthesis, and Antitumor Evaluation of Benzamide Derivatives Targeting HOXA1 Function.

HOXA1 is an oncogenic transcription factor that is overexpressed in multiple solid tumors and strongly associated with a poor prognosis. To date, no small-molecule agents have been reported to effectively target its function. In this study, a structure-based virtual screening approach led to the identification of a benzamide lead compound, F2, capable of binding to the key structural domain of HOXA1. Subsequent structure-activity relationship (SAR) optimization afforded a more potent derivative, F2-15. Mechanistic investigations revealed that F2-15 downregulates HOXA1 protein levels, thereby suppressing its transcriptional activity, altering downstream gene expression, and inducing DNA damage and apoptosis. In patient-derived xenograft (PDX) models of colorectal cancer and triple-negative breast cancer, F2-15 exhibited robust antitumor efficacy and showed synergistic activity in combination with cisplatin. These findings provide a strong rationale for the further development of F2-15 as a promising candidate for targeting HOXA1-driven malignancies.