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Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2022-07-19 , 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 1 , Lixue Chen 1 , Yanxia Li 2
Affiliation  

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.



中文翻译:


异丙基磺酰基取代的 2,4-二芳基氨基嘧啶衍生物的设计、合成和活性评价作为 FAK 抑制剂,用于潜在治疗胰腺癌



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。

更新日期:2022-07-22
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