2. Academic Validation
  3. Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer

  • Eur J Med Chem. 2022 Nov 5;241:114607. doi: 10.1016/j.ejmech.2022.114607.
Xu Zheng 1,  Xing Li 2,  Liangliang Tian 3,  Bin Wu 1,  Jiawen Yu 2,  Changyuan Wang 1,  Xiuli Sun 2,  Xiaodong Ma 4,  Lixue Chen 5,  Yanxia Li 6
Affiliations

Affiliations

  • 1 College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, PR China.
  • 2 Department of Hematology, Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China.
  • 3 School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 4 College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, PR China. Electronic address: xiaodong.ma@139.com.
  • 5 College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, PR China. Electronic address: chenlx2016@126.com.
  • 6 Department of Hematology, Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China. Electronic address: liyanxia001@163.com.
PMID: 35872546 DOI: 10.1016/j.ejmech.2022.114607
Abstract

A series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic Cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic Cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against immortalized normal human liver L-02 cells, indicating its low hepatotoxicity at an equivalent dosage. Furthermore, the elucidation of the mechanism of action revealed that compound 9h effectively inhibited cell migration and inhibited the proliferation of AsPC-1 by blocking the cell cycle at the G2/M phase. Moreover, 9h also demonstrated efficacy in inhibiting tumor growth in a murine AsPC-1 cell xenograft model at the dosage of 10 mg/kg without losing noticeable body weight. All these findings provide important clues for the identification of potent FAK inhibitors.

Keywords

2,4-diarylaminopyrimidines; Focal adhesion kinase (FAK); Isopropylsulfonyl; Pancreatic cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150730
    FAK Inhibitor
    FAK