2. Academic Validation
  3. Design, Synthesis, and Antitumor Evaluation of Benzamide Derivatives Targeting HOXA1 Function

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

  • J Med Chem. 2026 Feb 26;69(4):4090-4111. doi: 10.1021/acs.jmedchem.5c02745.
Yong-Jian Wang 1,  Xiao-Ning Yang 2,  Feng Wang 1,  Xiao-Fan Wu 1,  Yun-Jie Shi 3,  Ying Yang 4,  Xiao-Jiong Peng 1,  Hong Yi 1,  Ke Li 1,  Jian Yuan 5,  Zhuo-Rong Li 1,  Fanghua Gong 3,  Si-Tu Xue 1
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 3 School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China.
  • 4 Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 5 Cancer Research Center, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200331, China.
PMID: 41701908 DOI: 10.1021/acs.jmedchem.5c02745
Abstract

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.

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