Design, synthesis and evaluation of nitric oxide releasing derivatives of 2,4-diaminopyrimidine as novel FAK inhibitors for intervention of metastatic triple-negative breast cancer

  • Eur J Med Chem. 2023 Mar 15;250:115192. doi: 10.1016/j.ejmech.2023.115192.
Jinlin Zhang  1 ,  Kangping Xu  1 ,  Fei Yang  1 ,  Yaoren Qiu  1 ,  Jiayi Li  1 ,  Jing Li  1 ,  Wenxuan Wang  1 ,  Guishan Tan  1 ,  Zhenxing Zou  2 ,  Fenghua Kang  3
Affiliations
  • 1. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China.
  • 2. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China. Electronic address: [email protected].
  • 3. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China. Electronic address: [email protected].
PMID: 36801517 DOI: 10.1016/j.ejmech.2023.115192
Abstract

To search for novel medicines for intervention of triple-negative breast Cancer (TNBC), a series of phenylsulfonyl furoxan-based 2,4-diaminopyrimidine derivatives (8a-t) were designed and synthesized based on blocking FAK-mediated signaling pathways through both kinase-dependent and -independent manners. The most active compound 8f not only significantly inhibited FAK kinase activity (IC50 = 27.44 nM), displayed potent inhibitory effects on the proliferation (IC50 = 0.126 μM), invasion and migration of MDA-MB-231 cells, superior to the most widely studied FAK Inhibitor, TAE226, bearing 2,4-diaminopyrimidine, but also released high levels of NO, contributing to blockage of FAK mediated-signaling pathways by upregulating of p53 as well as suppressing the Y397 phosphorylation and its downstream effectors, including p-Akt, MMP-2, and MMP-9 via kinase-independent manner, leading to Apoptosis induction and decrease of FAs and SFs in TNBC cells. Importantly, 8f inhibited the lung metastasis of TNBC in vivo. Together, 8f may serve as a promising candidate for the treatment of metastatic TNBC.

Keywords
2,4-Diaminopyrimidine; Anti-metastasis activity; FAK inhibitor; Nitric oxide; Triple-negative breast cancer.
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