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Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-22 , DOI: 10.1021/acs.jmedchem.1c01014
Christopher J Zerio 1 , Tyler A Cunningham 2 , Allison S Tulino 1 , Erin A Alimusa 1 , Thomas M Buckley 1 , Kohlson T Moore 1 , Matthew Dodson 1 , Nathan C Wilson 1 , Andrew J Ambrose 1 , Taoda Shi 1 , Jared Sivinski 1 , Derek J Essegian 2 , Donna D Zhang 1 , Stephan C Schürer 2, 3 , Jonathan H Schatz 3, 4 , Eli Chapman 1
Affiliation  

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 28, which decreased BJAB Burkitt lymphoma cell viability. Biochemical and cellular studies, molecular docking, and functional assays uncovered that 28 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.

中文翻译:

发现具有新作用机制的 eIF4A 抑制剂

增加蛋白质合成是恶性生长的必要条件,因此,翻译已成为癌症的药物靶点。帽依赖性翻译的启动由真核起始因子 (eIF)4A 酶促驱动,eIF 是一种 ATP 驱动的 DEAD-box RNA 解旋酶,可解开起始密码子上游的信使 RNA 二级结构,从而实现下游基因的翻译。筛选 eIF4A ATPase 活性抑制剂产生了一个有趣的结果,令人惊讶的是,它没有 ATP 竞争性。一项药物化学运动产生了新型 eIF4A 抑制剂28,它降低了 BJAB Burkitt 淋巴瘤细胞的活力。生化和细胞研究、分子对接和功能分析发现28是一种 RNA 竞争性、ATP 非竞争性抑制剂,它在 eIF4A 的 RNA 凹槽中接合一个新的口袋,并通过干扰适当的 RNA 结合和抑制 ATP 水解来抑制解旋活动。通过这种独特的机制抑制 eIF4A 可能会提供新的策略来针对许多致癌途径的这个有希望的交叉点。
更新日期:2021-11-11
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