2. Academic Validation
  3. Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation

Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation

  • J Med Chem. 2012 Apr 12;55(7):3285-306. doi: 10.1021/jm201734r.
Richard A Ward 1,  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
Affiliations

Affiliation

  • 1 Oncology and Discovery Sciences iMEDs, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. richard.a.ward@astrazeneca.com
PMID: 22417091 DOI: 10.1021/jm201734r
Abstract

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.

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