Fragment Growing and Linking Lead to Novel Nanomolar Lactate Dehydrogenase Inhibitors

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• 作者：Anna Kohlmann ; Stephan G. Zech ; Feng Li ; Tianjun Zhou ; Rachel M. Squillace ; Lois Commodore ; Matthew T. Greenfield ; Xiaohui Lu ; David P. Miller ; Wei-Sheng Huang ; Jiwei Qi ; R. Mathew Thomas ; Yihan Wang ; Sen Zhang ; Rory Dodd ; Shuangying Liu ; Rongsong Xu ; Yongjin Xu ; Juan J. Miret ; Victor Rivera ; Tim Clackson ; William C. Shakespeare ; Xiaotian Zhu ; David C. Dalgarno
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1023-1040
• 全文大小：821K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (K_d) and enzyme inhibition (IC₅₀) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.