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Published on: December 1, 2016
Dichloroacetophenone biphenylsulfone ethers as anticancer pyruvate dehydrogenase kinase inhibitors in non-small cell
Yizhen Guo1, Yan Zhou1, Puhua Wu1
1Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Abstract:
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.
Insights
New dichloroacetophenone biphenylsulfone ethers show potent inhibition of pyruvate dehydrogenase kinase 1 (PDK1). Compound 31 effectively suppressed non-small-cell lung cancer (NSCLC) growth in vitro and in vivo, suggesting a promising new therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Pyruvate dehydrogenase kinase 1 (PDK1) is frequently overexpressed in cancers, including non-small-cell lung cancer (NSCLC).
- Targeting PDK1 is a potential anticancer strategy due to its role in cancer metabolism.
Purpose of the Study:
- To develop novel dichloroacetophenone biphenylsulfone ethers as PDK1 inhibitors.
- To evaluate the anticancer efficacy of compound 31 in NSCLC models.
Main Methods:
- Synthesis and PDK1 inhibition assays of novel compounds.
- In vitro studies using NSCLC cell lines (NCI-H1299, NCI-H1975) to assess IC50, colony formation, mitochondrial membrane potential, apoptosis, glucose metabolism, lactate levels, and reactive oxygen species (ROS).
- In vivo efficacy study using an NCI-H1975 mouse xenograft model.
Main Results:
- Compounds 30, 31, and 32 demonstrated significant PDK1 inhibition.
- Compound 31 exhibited sub-micromolar IC50 values in NSCLC cell lines.
- 31 suppressed tumor growth in a xenograft model, showing superior efficacy to the reference compound 64.
Conclusions:
- Dichloroacetophenone biphenylsulfone ethers are effective PDK1 inhibitors.
- Compound 31 displays significant anticancer activity against NSCLC, warranting further investigation.
- PDK1 inhibition represents a viable therapeutic approach for NSCLC treatment.
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