Pyruvate dehydrogenase kinase 1 (PDK1)是一种重要的代谢酶，在许多癌症类型中经常过度表达，包括非小细胞肺癌（NSCLC）。针对PDK1似乎是一种有吸引力的抗癌策略。基于以前报道的中等效力的抗癌PDK1抑制剂64，我们开发了三种二氯乙酰苯酮联苯磺酸醚30、31和32，它们分别在10μM时显示出74％、83％和72％的强PDK1抑制作用。然后我们在两种NSCLC细胞系，即NCI-H1299和NCI-H1975中研究了31的抗癌效果。结果发现，31表现出亚微米癌细胞IC50值，抑制了克隆形成，诱导线粒体膜电位去极化，诱导细胞凋亡，改变细胞葡萄糖代谢，并伴随着NSCLC细胞外乳酸水平的降低和活性氧的生成增强。此外，31显著抑制了在NCI-H1975小鼠异种移植模型中的肿瘤生长，胜过了64的抗癌效果。综上所述，我们的结果表明，通过二氯乙酰苯酮联苯磺酸醚抑制PDK1可能提供一种新的方法导向NSCLC治疗的备选治疗选择。 Copyright © 2023. Published by Elsevier B.V.

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 IC50s, 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.Copyright © 2023. Published by Elsevier B.V.