Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors

Yifu Liu; Zuoquan Xie; Dan Zhao; Jin Zhu; Fei Mao; Shuai Tang; Hui Xu; Cheng Luo; Meiyu Geng; Min Huang; Jian Li

doi:10.1021/acs.jmedchem.6b01245

Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors

J Med Chem. 2017 Mar 23;60(6):2227-2244. doi: 10.1021/acs.jmedchem.6b01245. Epub 2017 Mar 6.

Authors

Yifu Liu¹, Zuoquan Xie², Dan Zhao³, Jin Zhu¹, Fei Mao¹, Shuai Tang², Hui Xu², Cheng Luo³, Meiyu Geng², Min Huang², Jian Li¹

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
² Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.

PMID: 28230989
DOI: 10.1021/acs.jmedchem.6b01245

Abstract

Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (k_inact/K_i = 4.17 × 10³ M^-1 s^-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.

MeSH terms

A549 Cells
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Disulfides / chemistry*
Disulfides / pharmacology*
Disulfides / therapeutic use
Female
Glucose / metabolism
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Models, Molecular
Molecular Docking Simulation
Morpholines / chemistry*
Morpholines / pharmacology*
Morpholines / therapeutic use
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase

Substances

Antineoplastic Agents
Disulfides
Morpholines
PDK1 protein, human
PDK2 protein, human
Pdk1 protein, mouse
Pdk2 protein, mouse
Protein Kinase Inhibitors
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
bis(4-morpholinyl thiocarbonyl)disulfide
Protein Serine-Threonine Kinases
Glucose