2. Academic Validation
  3. Discovery of novel chloropyramine-cinnamic acid hybrids as potential FAK inhibitors for intervention of metastatic triple-negative breast cancer

Discovery of novel chloropyramine-cinnamic acid hybrids as potential FAK inhibitors for intervention of metastatic triple-negative breast cancer

  • Bioorg Med Chem. 2022 Jul 15;66:116809. doi: 10.1016/j.bmc.2022.116809.
Fei Yang 1,  Kangping Xu 1,  Sha Zhang 1,  Jinlin Zhang 1,  Yaoren Qiu 1,  Jin Luo 1,  Guishan Tan 1,  Zhenxing Zou 1,  Wenxuan Wang 2,  Fenghua Kang 3
Affiliations

Affiliations

  • 1 Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China.
  • 2 Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China. Electronic address: [email protected].
  • 3 Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China. Electronic address: [email protected].
PMID: 35569251 DOI: 10.1016/j.bmc.2022.116809
Abstract

To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast Cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing Apoptosis of TNBC cells. Together, 7d is a novel FAK Inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.

Keywords

Anti-metastasis activity; Chloropyramine; FAK inhibitor; Formation of focal adhesion; Triple-negative breast cancer.

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