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Discovery of Pyruvate Dehydrogenase kinase inhibitors Made New Progress
Update time: 2015-11-10
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Scientists from Shanghai Institute of Materia Medica (SIMM) and East China University of Science and Technology jointly made new progress in the discovery of anticancer drugs targeting cancer metabolism. The team discovered the first covalent inhibitor against mitochondrial pyruvate dehydrogenase kinase (PDK, PDHK), a molecular switch critically regulating glycolytic metabolism in cancer cells, and demonstrated its promise in cancer treatment.

Cancer cells feature a unique metabolic profile of high aerobic glycolysis, also known as “Warburg effect”, which describes the phenomenon of the enhanced conversion of glucose into lactate even in the presence of oxygen. Aerobic glycolysis confers a significant growth advantage of cancer cells by supplying essential ATP production, generating precursors for biosynthesis and providing reducing equivalents for antioxidant defense, and has been recognized as a hallmark of cancer. Mitochondrial pyruvate dehydrogenase kinase (PDK, PDHK) functions as a molecular switch that diminishes mitochondrial respiration and enhances aerobic glycolysis in cancer cells. PDK is the most extensively investigated anticancer targets in the aerobic glycolysis pathway, but most inhibitors are still at early stage preclinical research and lack of therapeutic potentials.

In an effort to explore therapeutic opportunities in targeting PDK, scientists from SIMM and East China University of Science and Technology jointly discovered the first covalent PDK inhibitor designated as JX06, which exhibited remarkable potency against PDK1 and promising anticancer activity in aerobic glycolysis highly dependent cancer subset. The mechanism involves a previously unappreciated cysteine, which impacts the enzymatic activity of PDK1 via affecting the ATP binding pocket. The study also identified a hydrophobic pocket adjacent to this cysteine residue, which provided a venue for small molecules to approach the cysteine for chemical modification. These findings open the possibility for the rational design of PDK covalent inhibitors.

This study also solved a long puzzle whether there exists some cancer subset that is more responsive to glycolysis inhibition. The study showed that the intrinsic glucose metabolic status varied among the cell lines and determined their responsiveness to PDHK inhibition. The ratio of Extracellular acidification rate (ECAR) to oxygen consumption rate (OCR) may be used to stratify cancer subset sensitive to glycolysis inhibition and may facilitate the translation of metabolic-modulating drugs to therapeutic benefits. This finding was published in Cancer Research (online on Oct 19, 2015).

This work was supported by the National Natural Science Foundation of China and the Ministry of Science and Technology of China.


Pyruvate dehydrogenase kinase PDK1 (PDHK1) is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at R286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue.

Keywords: Cancer metabolism, Aerobic glycolysis, Pyruvate dehydrogenase kinase, Covalent inhibitors

Correspondence: GENG Meiyu, Tel: 021-50805875


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Figure by SIMM: A scheme showing proposed mechanism of JX06 in PDK1 inhibition




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