5W8K
Crystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 29 and NADH
Summary for 5W8K
| Entry DOI | 10.2210/pdb5w8k/pdb |
| Descriptor | L-lactate dehydrogenase A chain, 2-{3-(3,4-difluorophenyl)-5-hydroxy-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, ... (6 entities in total) |
| Functional Keywords | oxidoreductase, oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm: P00338 |
| Total number of polymer chains | 4 |
| Total formula weight | 152887.50 |
| Authors | Lukacs, C.M.,Dranow, D.M. (deposition date: 2017-06-21, release date: 2018-01-17, Last modification date: 2024-04-03) |
| Primary citation | Rai, G.,Brimacombe, K.R.,Mott, B.T.,Urban, D.J.,Hu, X.,Yang, S.M.,Lee, T.D.,Cheff, D.M.,Kouznetsova, J.,Benavides, G.A.,Pohida, K.,Kuenstner, E.J.,Luci, D.K.,Lukacs, C.M.,Davies, D.R.,Dranow, D.M.,Zhu, H.,Sulikowski, G.,Moore, W.J.,Stott, G.M.,Flint, A.J.,Hall, M.D.,Darley-Usmar, V.M.,Neckers, L.M.,Dang, C.V.,Waterson, A.G.,Simeonov, A.,Jadhav, A.,Maloney, D.J. Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). J. Med. Chem., 60:9184-9204, 2017 Cited by PubMed Abstract: We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target. PubMed: 29120638DOI: 10.1021/acs.jmedchem.7b00941 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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