具有全新结构的三阴性乳腺癌新靶点eEF2K激酶抑制剂的设计、合成及活性评价

Triple-negative breast cancer (TNBC) is a high risk cancer type in clinics. Currently, there is no specific drug for treating TNBC on the market worldwide. Chemotherapy has been the main TNBC therapy, but its effectiveness is limited and patients often develop drug resistance quickly. Thus, new drugs for TNBC treatment are highly demanded. Encouragingly, a recent study revealed that PTEN/p53 deficient TNBC tumors were highly sensitive to eEF2K inhibitors. The tumor growth was notably inhibited both in vitro and in vivo, suggesting that eEF2K can be a highly valuable target to treat TNBC. Motivated by this result, we have successfully discovered 5 new eEF2K small molecule inhibitors, all with novel structures, using an advanced high through-put virtual screening technique by screening a library of 3,000,000 compounds. Further, by assistance of the advanced long timescale molecular dynamics simulation and free energy calculation, we have designed 5 classes of their derivatives. We propose to carry out the synthesis of the compounds, and evaluate their activities both in vitro and in vivo; discovery 2-4 small molecule inhibitors which are novel, highly effective and selective against eEF2K, and 1-2 drug candidates; and with the assistance of state-of-the-art computational techniques, summarizing the structure-activity-relationship between eEF2K and the compounds in aid of subsequent studies.

三阴性乳腺癌（TNBC）是临床上极具代表性的高危肿瘤类型，目前世界上还没有针对其的有效上市药物，临床治疗以化疗为主，但化疗效果差并易产生耐药性，因此TNBC是一个迫切需要解决的医药难题，亟待发展更加有效的治疗方法。最新的研究表明eEF2K激酶抑制剂在细胞及动物模型中都对PTEN/p53缺失的TNBC具有明显的抑制作用，提示其作为TNBC靶向治疗的医疗潜力。在此背景下，本项目前期通过先进的高通量虚拟筛选，已经成功从三百万个小分子中得到5个结构新颖且具有eEF2K抑制活性的小分子；并运用长时间尺度的分子动力学模拟和自由能计算等高级计算机辅助技术，设计了该5类目标化合物。本项目拟完成化合物的合成并评价其体内外活性。通过项目的开展，争取发现2-4个结构新颖、强效、高选择性的化合物，力争得到1-2个候选药物分子；并总结eEF2K与化合物的构效关系，揭示抑制剂的作用机制，为后续研究提供科学依据。

三阴性乳腺癌（TNBC）是临床上极具代表性的高危肿瘤类型，目前世界上还没有针对其的有效上市药物，临床治疗以化疗为主，但化疗效果差并易产生耐药性，因此TNBC是一个迫切需要解决的医药难题，亟待发展更加有效的治疗方法。最新的研究表明eEF2K激酶抑制剂在细胞及动物模型中都对PTEN/p53缺失的TNBC具有明显的抑制作用，提示其作为TNBC靶向治疗的医疗潜力。本项目通过计算机辅助技术得到的6类化合物，并完成了其合成与体外评价工作，其中有一类化合物在已报道的eEF2K抑制剂中具有最高的体外酶活性（IC50=117nM）。初步的小鼠体内三阴性乳腺癌细胞肺转移模型显示该化合物具有一定的抗转移活性。