Journal ArticleDOI
Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors
Liu Yifu,Zuoquan Xie,Dan Zhao,Jin Zhu,Fei Mao,Shuai Tang,Hui Xu,Cheng Luo,Meiyu Geng,Min Huang,Jian Li +10 more
TLDR
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.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 (kinact/Ki = 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.read more
Citations
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Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
Matthias Gehringer,Stefan Laufer +1 more
TL;DR: An overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands is provided, with special emphasis on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
Journal ArticleDOI
Advances in covalent kinase inhibitors.
TL;DR: A comprehensive overview of covalent kinase inhibitors reported in the literature over a decade period, 2007-2018 is provided, with emphasis on the rationale behind warhead choice, optimization approach, and inhibitor design.
Journal ArticleDOI
Polysulfurating reagent design for unsymmetrical polysulfide construction.
TL;DR: A library of broad-spectrum polysulfurating reagent affording unsymmetrical di- and tri-sulfides under mild conditions, suitable for late-stage modification of natural products and pharmaceuticals is designed and scalably synthesized.
Journal ArticleDOI
Overview of Recent Strategic Advances in Medicinal Chemistry
Gaochan Wu,Tong Zhao,Dongwei Kang,Jian Zhang,Yu'ning Song,Vigneshwaran Namasivayam,Jacob Kongsted,Christophe Pannecouque,Erik De Clercq,Vasanthanathan Poongavanam,Xinyong Liu,Peng Zhan +11 more
TL;DR: This Perspective aims to present a "big-picture" overview of recent strategic innovations in medicinal chemistry and drug discovery.
Journal ArticleDOI
Metabolic Flexibility in Cancer: Targeting the Pyruvate Dehydrogenase Kinase:Pyruvate Dehydrogenase Axis.
TL;DR: The goal of this review is to understand the regulation of the PDK isozyme family, their role in cancer proliferation, and how to target this pathway therapeutically to specifically and effectively reduce cancer growth.
References
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TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
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Garrett M. Morris,David S. Goodsell,Robert Scott Halliday,Ruth Huey,William E. Hart,Richard K. Belew,Arthur J. Olson +6 more
TL;DR: It is shown that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckia genetic algorithm is the most efficient, reliable, and successful of the three.
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HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia
TL;DR: A hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production is revealed.
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HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
TL;DR: It is shown by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.
Journal ArticleDOI
The resurgence of covalent drugs
TL;DR: The prevalence and pharmacological advantages of covalent drugs are surveyed, how potential risks and challenges may be addressed through innovative design, and the broad opportunities provided by targeted covalENT inhibitors are presented.