2. Academic Validation
  3. Design, synthesis and biological evaluation of coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer

Design, synthesis and biological evaluation of coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer

  • Bioorg Med Chem Lett. 2025 Aug 1:123:130240. doi: 10.1016/j.bmcl.2025.130240.
Mengrong Lei 1,  Hanxue Huang 1,  Jiayi Li 2,  Jinlin Zhang 2,  Geng Yu 2,  Xin Jin 1,  Junyan Liu 3,  Fenghua Kang 4,  Zhaoqian Liu 5
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China.
  • 2 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, PR China.
  • 3 Department of orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, PR China.
  • 4 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, PR China. Electronic address: kangfenghua@csu.edu.cn.
  • 5 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, PR China. Electronic address: zqliu@csu.edu.cn.
PMID: 40228675 DOI: 10.1016/j.bmcl.2025.130240
Abstract

A series of hybrids (8a-h and 11a-h) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung Cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound 8a was identified as the most active compound with IC50 value of 0.28 μM in H1299 cells, superior to TAE226 (IC50 = 2.28 μM). In addition, 8a was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, 8a exhibited potent kinase inhibitory activity of FAK (IC50 = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, 8a was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, 8a may be a promising candidate for the treatment of NSCLC.

Keywords

2,4-diphenylpyrimidine; Anti-cancer activity; Coumarin; FAK inhibitor; NSCLC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173603
    FAK Inhibitor
    FAK