Yang Ronghua, Guo Caihong
Department of Thoracic Surgery , The Affiliated Hospital of Qingdao University , Qingdao , Shandong , China.
Department of Respiratory Medicine , The Affiliated Hospital of Qingdao University , Qingdao , Shandong , China . Email:
Medchemcomm. 2018 Sep 24;9(11):1843-1849. doi: 10.1039/c8md00453f. eCollection 2018 Nov 1.
Targeting pyruvate dehydrogenase kinases (PDKs) reverses the Warburg effect, which could be a potential therapeutic target for anti-cancer drug discovery. In this paper, we identified 12 potential PDK inhibitors by virtual ligand screening of a chemical library, and then further verified them by an enzymatic assay, in which , , and strongly inhibited the function of PDKs, with IC values of 1.26, 0.62, and 0.41 μM against PDK1, respectively, and showed a similar inhibitory effect on PDK2, PDK3, and PDK4. However, we failed to correlate the observed inhibitory activity against PDKs with cellular activity under normal conditions. In contrast, and inhibited NCI-H1975 cell proliferation under hypoxia, with EC values of 4.66 and 3.88 μM, respectively, suggesting that and could be promising leads for further development of PDK inhibitors in cancer treatment.
靶向丙酮酸脱氢酶激酶（PDKs）可逆转瓦伯格效应，这可能是抗癌药物研发的一个潜在治疗靶点。在本文中，我们通过对一个化学文库进行虚拟配体筛选，鉴定出12种潜在的PDK抑制剂，然后通过酶活性测定进一步验证它们，其中， 、 和 强烈抑制PDKs的功能，对PDK1的IC值分别为1.26、0.62和0.41 μM，并且对PDK2、PDK3和PDK4显示出类似的抑制作用。然而，在正常条件下，我们未能将观察到的对PDKs的抑制活性与细胞活性联系起来。相比之下， 和 在缺氧条件下抑制NCI-H1975细胞增殖，EC值分别为4.66和3.88 μM，这表明 和 可能是癌症治疗中进一步开发PDK抑制剂的有前景的先导化合物。
