Warburg effect, a preference of aerobic glycolysis for energy production even in the presence of adequate oxygen, is one of the most prominent distinctions of cancer cells from their normal equivalents. Upregulated pyruvate dehydrogenase kinase 1 (PDK1) was found to dominate the pivotal switch from mitochondrial respiration to aerobic glycolysis by inactivating pyruvate dehydrogenase (PDH) in cancer cells. PDK1 inhibition may lead to an unfavorable environment for cancer cells, which presents an opportunity for anticancer therapy. However, up to now, only limited number of PDK1 inhibitors were reported. In this work, we reported our attempt to discover novel small molecules from a diverse chemical library containing 15 000 small molecules selected from the Chembridge screening library. We developed a kinase activity-based high throughput screening (HTS) assay for initial screening of PDK1 inhibitors. Seven PDK1 inhibitory compounds were identified with IC₅₀ values range from 0.68 and 45.69 μM. Follow up evaluations on these compounds revealed good PDK1 binding affinity and antiproliferative activities in cancer cell lines, with two novel hits (9 and 10) clearly outperformed others compounds in terms of PDK1 inhibition and the suppression of cancer cell proliferation. 9 and 10 may serve as new chemistry starting points for further structural modifications to improve the potency on PDK1 inhibition for anticancer treatment.

中文翻译：

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基于激酶活性的高通量筛选用于抗癌药物的新型丙酮酸脱氢酶激酶1（PDK1）抑制剂的鉴定。

Warburg效应是有氧糖酵解对能量产生的一种偏好，即使在充足的氧气存在下，Warburg效应也是癌细胞与其正常等同物最显着的区别之一。发现上调的丙酮酸脱氢酶激酶1（PDK1）通过灭活癌细胞中的丙酮酸脱氢酶（PDH）主导了从线粒体呼吸到有氧糖酵解的关键转换。抑制PDK1可能导致癌细胞处于不利环境，这为抗癌治疗提供了机会。然而，到目前为止，仅报道了数量有限的PDK1抑制剂。在这项工作中，我们报告了我们从包含Chembridge筛选库中选出的15 000个小分子的多样化化学库中发现新颖小分子的尝试。我们开发了一种基于激酶活性的高通量筛选（HTS）检测方法，用于PDK1抑制剂的初步筛选。用IC鉴定了7种PDK1抑制性化合物_50个值的范围为0.68和45.69μM。对这些化合物的后续评估显示了在癌细胞系中良好的PDK1结合亲和力和抗增殖活性，在抑制PDK1和抑制癌细胞增殖方面，两个新的命中物（9和10）明显优于其他化合物。图9和图10可以用作新的化学起点，用于进一步的结构修饰，以提高对PDK1抑制的抗癌作用。