Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation
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- 作者：Richard A. Ward ; Claire Brassington ; Alexander L. Breeze ; Alessandro Caputo ; Susan Critchlow ; Gareth Davies ; Louise Goodwin ; Giles Hassall ; Ryan Greenwood ; Geoffrey A. Holdgate ; Michael Mrosek ; Richard A. Norman ; Stuart Pearson ; Jonathan Tart ; Julie A. Tucker ; Martin Vogtherr ; David Whittaker ; Jonathan Wingfield ; Jon Winter ; Kevin Hudson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：April 12, 2012
- 年：2012
- 卷：55
- 期：7
- 页码：3285-3306
- 全文大小：854K
- 年卷期：v.55,no.7(April 12, 2012)
- ISSN：1520-4804
文摘
Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.