基于结构的新型 PRMT5 抑制剂用于非小细胞肺癌的发现和生物学检测。
Structure-Based Discovery and Biological Assays of a Novel PRMT5 Inhibitor for Non-Small Cell Lung Cancer.
机构信息
Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China.
Dr Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR 999078, China.
出版信息
Molecules. 2022 Nov 1;27(21):7436. doi: 10.3390/molecules27217436.
Protein arginine methyltransferase 5 (PRMT5) is a popular anticancer target that regulates histone or nonhistone methylation and is linked to the development and poor prognosis of non-small cell lung cancer. PRMT5 inhibitors have shown great promise in clinical trials as a cancer therapy. However, most inhibitors reported recently act in a SAM-competitive mode and lack structural diversity. In this paper, a novel non-SAM inhibitor, 3039-0164, was discovered by the structure-based virtual screening method. The binding mechanism of 3039-0164 to PRMT5 was revealed via molecular docking and molecular dynamics simulations. 3039-0164 inhibited PRMT5 enzymatic activity, downregulated the expression of PRMT5 downstream target genes (FGFR3 and eIF4E), and blocked the activation of the PI3K/AKT/mTOR and ERK signaling pathways. The discovery of 3039-0164 provides precise and creative hit compounds for the design optimization of PRMT5 lead compounds in non-small cell lung cancer.
蛋白质精氨酸甲基转移酶 5（PRMT5）是一种热门的抗癌靶点，可调节组蛋白或非组蛋白甲基化，与非小细胞肺癌的发生和不良预后有关。PRMT5 抑制剂在临床试验中作为癌症治疗方法显示出巨大的前景。然而，最近报道的大多数抑制剂以 SAM 竞争性模式起作用，并且缺乏结构多样性。在本文中，通过基于结构的虚拟筛选方法发现了一种新型非-SAM 抑制剂 3039-0164。通过分子对接和分子动力学模拟揭示了 3039-0164 与 PRMT5 的结合机制。3039-0164 抑制 PRMT5 的酶活性，下调 PRMT5 下游靶基因（FGFR3 和 eIF4E）的表达，并阻断 PI3K/AKT/mTOR 和 ERK 信号通路的激活。3039-0164 的发现为非小细胞肺癌中 PRMT5 先导化合物的设计优化提供了精确而有创意的命中化合物。
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