JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification

  • Cancer Res. 2015 Nov 15;75(22):4923-36. doi: 10.1158/0008-5472.CAN-15-1023.
Wenyi Sun  1 ,  Zuoquan Xie  1 ,  Yifu Liu  2 ,  Dan Zhao  3 ,  Zhixiang Wu  4 ,  Dadong Zhang  1 ,  Hao Lv  1 ,  Shuai Tang  1 ,  Nan Jin  1 ,  Hualiang Jiang  3 ,  Minjia Tan  4 ,  Jian Ding  1 ,  Cheng Luo  5 ,  Jian Li  6 ,  Min Huang  7 ,  Meiyu Geng  7
Affiliations
  • 1. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 3. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4. The Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected] [email protected] [email protected] [email protected].
  • 6. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. [email protected] [email protected] [email protected] [email protected].
  • 7. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected] [email protected] [email protected] [email protected].
PMID: 26483203 DOI: 10.1158/0008-5472.CAN-15-1023
Abstract

Pyruvate dehydrogenase kinase PDK1 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 Arginine 286 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.

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