Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation
Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation
复制标题
开发针对丙酮酸脱氢酶激酶和人乳酸脱氢酶 A 的双抑制剂：高通量虚拟筛选、合成和生物验证
DOI：
10.1016/j.ejmech.2020.112579
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发表时间：
2020
影响因子：
6.7
通讯作者：
Yun He
中科院分区：
文献类型：
--
作者：
Sichuan Xiang;Ding Huang;Qiaolin He;Jie Li;Kin Yip Tam;Shao-Lin Zhang;Yun He
Most cancer cells feature an altered glucose metabolism from oxidative phosphorylation to cytoplasmic glycolysis. Pyruvate dehydrogenase kinases (PDKs) and lactate dehydrogenase A (LDHA) play crucial roles in promotion of glycolysis, thus the inhibition of both enzymes is considered a promising strategy for developing of anticancer therapeutics. Herein, we describe the first discovery of series novel dual inhibitors targeting PDKs and LDHA. We identified 6 hits from a library database containing 485465 compounds through a high-throughput virtual screening assay. Hit-to-lead optimization enabled us to discover two compounds, namely20eand20k, which inhibited PDKs with IC50values of 0.8, and 1.6 μM, respectively, and inhibited LDHA with IC50values of 0.15 and 0.7 μM, respectively. Meanwhile, the two compounds reduced A549 cell proliferation with EC50values of 13.2, and 15.7 μM. Furthermore,20eand20kdecreased the lactate formation, and increased oxygen consumption, suggesting the two compounds modulated the glucose metabolic pathways in cancer cells.
