College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
Miller School of Medicine, Department of Molecular and Cellular Pharmacology, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States.
J Med Chem. 2021 Nov 11;64(21):15727-15746. doi: 10.1021/acs.jmedchem.1c01014. Epub 2021 Oct 22.
Increased protein synthesis is a requirement for malignant growth, and as a result, translation has become a pharmaceutical target for cancer. The initiation of cap-dependent translation is enzymatically driven by the eukaryotic initiation factor (eIF)4A, an ATP-powered DEAD-box RNA-helicase that unwinds the messenger RNA secondary structure upstream of the start codon, enabling translation of downstream genes. A screen for inhibitors of eIF4A ATPase activity produced an intriguing hit that, surprisingly, was not ATP-competitive. A medicinal chemistry campaign produced the novel eIF4A inhibitor , which decreased BJAB Burkitt lymphoma cell viability. Biochemical and cellular studies, molecular docking, and functional assays uncovered that is an RNA-competitive, ATP-uncompetitive inhibitor that engages a novel pocket in the RNA groove of eIF4A and inhibits unwinding activity by interfering with proper RNA binding and suppressing ATP hydrolysis. Inhibition of eIF4A through this unique mechanism may offer new strategies for targeting this promising intersection point of many oncogenic pathways.
蛋白质合成的增加是恶性生长的要求，因此，翻译已成为癌症的药物靶点。帽依赖性翻译的起始是由真核起始因子 (eIF)4A 酶促驱动的，eIF4A 是一种 ATP 驱动的 DEAD 盒 RNA 解旋酶，它解开起始密码子上游的信使 RNA 二级结构，从而使下游基因得以翻译。筛选 eIF4A ATP 酶活性抑制剂产生了一个有趣的发现，令人惊讶的是，它不是 ATP 竞争性抑制剂。一个药物化学研究产生了新型的 eIF4A 抑制剂 ，它降低了 BJAB 伯基特淋巴瘤细胞的活力。生化和细胞研究、分子对接和功能测定揭示了 是一种 RNA 竞争性、ATP 非竞争性抑制剂，它与 eIF4A 的 RNA 凹槽中的一个新口袋结合，并通过干扰正确的 RNA 结合和抑制 ATP 水解来抑制解旋活性。通过这种独特的机制抑制 eIF4A 可能为靶向这一多癌基因途径的有希望的交汇点提供新的策略。
