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.

设计并合成了一系列异丙磺酰基取代的2,4-二芳基氨基嘧啶衍生物作为FAK抑制剂，以评估其抗胰腺癌的生物活性。最有前途的化合物之一， 9h，有效干扰FAK介导的磷酸化并抑制人胰腺癌AsPC-1细胞的增殖，半数抑制浓度(IC ₅₀ )值分别为0.1165 nM和0.1596 μM。此外， 9h对永生化正常人肝L-02细胞也表现出相对较低的毒性，表明其在同等剂量下肝毒性较低。此外，作用机制的阐明表明，化合物9h通过阻断细胞周期在G2/M期，有效抑制细胞迁移并抑制AsPC-1的增殖。此外， 9h还在小鼠 AsPC-1 细胞异种移植模型中显示出在 10 mg/kg 剂量下抑制肿瘤生长的功效，且体重没有明显下降。所有这些发现为鉴定有效的 FAK 抑制剂提供了重要线索。