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

• DOI: 10.1016/j.ejmech.2022.114607
• Publication Date: 2022-07-19T02:09:06Z
• Authors: Xu Zheng; Xing Li; Liangliang Tian; Bin Wu; Jiawen Yu; Changyuan Wang; Xiuli Sun; Xiaodong Ma; Lixue Chen; Yanxia Li
• Keywords: 0301 basic medicine; Antineoplastic Agents; 3. Good health; Pancreatic Neoplasms; Mice; 03 medical and health sciences; Pyrimidines; 0302 clinical medicine; Cell Line, Tumor; Focal Adhesion Protein-Tyrosine Kinases; Animals; Humans; Protein Kinase Inhibitors; Cell Proliferation

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.