6Q13

CRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00420737-09 AT 2.00 A RESOLUTION

Summary for 6Q13

• Entry DOI: 10.2210/pdb6q13/pdb
• Related: 6Q0D
• Descriptor: L-lactate dehydrogenase A chain, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-3-{3-[(5-methylthiophen-2-yl)ethynyl]phenyl}-1H-pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid, ... (5 entities in total)
• Functional Keywords: ldha, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 153000.40

Authors

Davies, D.R.,Dranow, D.M. (deposition date: 2019-08-02, release date: 2020-09-23, Last modification date: 2023-10-11)

Primary citation

Rai, G.,Urban, D.J.,Mott, B.T.,Hu, X.,Yang, S.M.,Benavides, G.A.,Johnson, M.S.,Squadrito, G.L.,Brimacombe, K.R.,Lee, T.D.,Cheff, D.M.,Zhu, H.,Henderson, M.J.,Pohida, K.,Sulikowski, G.A.,Dranow, D.M.,Kabir, M.,Shah, P.,Padilha, E.,Tao, D.,Fang, Y.,Christov, P.P.,Kim, K.,Jana, S.,Muttil, P.,Anderson, T.,Kunda, N.K.,Hathaway, H.J.,Kusewitt, D.F.,Oshima, N.,Cherukuri, M.,Davies, D.R.,Norenberg, J.P.,Sklar, L.A.,Moore, W.J.,Dang, C.V.,Stott, G.M.,Neckers, L.,Flint, A.J.,Darley-Usmar, V.M.,Simeonov, A.,Waterson, A.G.,Jadhav, A.,Hall, M.D.,Maloney, D.J.
Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.
J.Med.Chem., 63:10984-11011, 2020

PubMed Abstract: Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement , possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, drug-target residence times, and PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition . The lead compounds, named () and (), possess desirable attributes for further studying the effect of LDH inhibition.

PubMed: 32902275
DOI: 10.1021/acs.jmedchem.0c00916

Experimental method

X-RAY DIFFRACTION (2 Å)