Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
School of Dentistry, Shenzhen University Health Science, Center, Shenzhen, China.
Chem Biol Interact. 2023 Jun 1;378:110467. doi: 10.1016/j.cbi.2023.110467. Epub 2023 Mar 31.
Pyruvate dehydrogenase kinase 1 (PDK1) is an important metabolic enzyme which is often overexpressed in many types of cancers, including non-small-cell lung cancers (NSCLC). Targeting PDK1 appears to be an attractive anticancer strategy. Based on a previously reported moderate potent anticancer PDK1 inhibitor, 64, we developed three dichloroacetophenone biphenylsulfone ethers, 30, 31 and 32, which showed strong PDK1 inhibitions of 74%, 83% and 72% at 10 μM, respectively. Then we investigated the anticancer effects of 31 in two NSCLC cell lines, namely, NCI-H1299 and NCI-H1975. It was found that 31 exhibited sub-micromolar cancer cell IC50, suppressed colony formation, induced mitochondrial membrane potential depolarization, triggered apoptosis, altered cellular glucose metabolism, with concomitant reductions in extracellular lactate levels and enhanced the generation of reactive oxygen species in NSCLC cells. Moreover, 31 significantly suppressed the tumor growth in an NCI-H1975 mouse xenograft model, outperforming the anticancer effects of 64. Taken together our results suggested that inhibition of PDK1 via dichloroacetophenone biphenylsulfone ethers may provide a novel direction leading to an alternative treatment option in NSCLC therapy.
丙酮酸脱氢酶激酶 1（PDK1）是一种重要的代谢酶，在许多类型的癌症中经常过表达，包括非小细胞肺癌（NSCLC）。靶向 PDK1 似乎是一种有吸引力的抗癌策略。基于之前报道的中等活性的 PDK1 抑制剂 64，我们开发了三种二氯乙酰苯二苯砜醚 30、31 和 32，它们在 10μM 时对 PDK1 的抑制率分别为 74%、83%和 72%。然后，我们研究了 31 在两种 NSCLC 细胞系 NCI-H1299 和 NCI-H1975 中的抗癌作用。结果发现，31 对癌细胞的 IC50 表现出亚微米级，抑制集落形成，诱导线粒体膜电位去极化，引发细胞凋亡，改变细胞葡萄糖代谢，同时降低细胞外乳酸水平，并增强 NSCLC 细胞中活性氧的产生。此外，31 在 NCI-H1975 小鼠异种移植模型中显著抑制肿瘤生长，优于 64 的抗癌效果。综上所述，通过二氯乙酰苯二苯砜醚抑制 PDK1 可能为 NSCLC 治疗提供一种新的治疗选择。
