2. Academic Validation
  3. Structure-based modification of carbonyl-diphenylpyrimidines (Car-DPPYs) as a novel focal adhesion kinase (FAK) inhibitor against various stubborn cancer cells

Structure-based modification of carbonyl-diphenylpyrimidines (Car-DPPYs) as a novel focal adhesion kinase (FAK) inhibitor against various stubborn cancer cells

  • Eur J Med Chem. 2019 Jun 15:172:154-162. doi: 10.1016/j.ejmech.2019.04.004.
Luhong Wang 1,  Min Ai 2,  Jiawen Yu 3,  Lingling Jin 2,  Changyuan Wang 2,  Zhihao Liu 4,  Xiaohong Shu 2,  Zeyao Tang 2,  Kexin Liu 2,  Hui Luo 5,  Wenshun Guan 5,  Xiuli Sun 6,  Xiaodong Ma 7
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, PR China.
  • 2 College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, PR China.
  • 3 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China.
  • 4 College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
  • 5 Liaoning Ben-healthy Natural Technology and Dalian Buyun Biotechnology Co., Ltds., 116085, PR China.
  • 6 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China. Electronic address: sunxl0411@163.com.
  • 7 College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, PR China. Electronic address: xiaodong.ma@139.com.
PMID: 30978560 DOI: 10.1016/j.ejmech.2019.04.004
Abstract

A family of carbonyl-substituted diphenylpyrimidine derivatives (Car-DPPYs) with strong activity against focal adhesion kinase (FAK), were described in this manuscript. Among them, compounds 7a (IC50 = 5.17 nM) and 7f (IC50 = 2.58 nM) displayed equal anti-FAK enzymatic activity to the lead compound TAE226 (6.79 nM). In particular, compound 7a also exhibited strong antiproliferative activity against several stubborn Cancer cells, including AsPC-1 cells (IC50 = 0.105 μM), BxPC-3 cells (IC50 = 0.090 μM), and MCF-7/ADR cells (IC50 = 0.59 μM). Additionally, compound 7a also showed great antitumor efficacy in vivo via aAsPC-1 Cancer Xenograft mouse model. The preliminary mechanism study by Western blot analysis revealed that 7a repressed FAK phosphorylation in AsPC Cancer cells. Taken together, the results indicate that compound 7a may serve as a promising preclinical candidate for treatment of stubborn cancers.

Keywords

Activity; Cancer; FAK; Inhibitor; Pyrimidine.

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