title: Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation.
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.
authors.affiliation: Oncology and Discovery Sciences iMEDs, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. richard.a.ward@astrazeneca.com
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ward
authors.forename: Claire
authors.initials: C
authors.lastname: Brassington
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Breeze
authors.forename: Alessandro
authors.initials: A
authors.lastname: Caputo
authors.forename: Susan
authors.initials: S
authors.lastname: Critchlow
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.forename: Louise
authors.initials: L
authors.lastname: Goodwin
authors.forename: Giles
authors.initials: G
authors.lastname: Hassall
authors.forename: Ryan
authors.initials: R
authors.lastname: Greenwood
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Holdgate
authors.forename: Michael
authors.initials: M
authors.lastname: Mrosek
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
authors.forename: Stuart
authors.initials: S
authors.lastname: Pearson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tart
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Martin
authors.initials: M
authors.lastname: Vogtherr
authors.forename: David
authors.initials: D
authors.lastname: Whittaker
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wingfield
authors.forename: Jon
authors.initials: J
authors.lastname: Winter
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D057075:Enzyme Assays; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D000080864:Lactate Dehydrogenase 5; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009536:Niacinamide / Q000737:chemistry; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D007527:Isoenzymes; D008314:Malonates; D009536:Niacinamide; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D010072:Oxamic Acid