6Q0D

CRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00384414-01 AT 2.05 A RESOLUTION

6Q0D の概要

• エントリーDOI: 10.2210/pdb6q0d/pdb
• 分子名称: L-lactate dehydrogenase A chain, PHOSPHATE ION, 2-{3-[3-(cyclopentylethynyl)-4-fluorophenyl]-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: ldha, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 229259.30

構造登録者

Dranow, D.M.,Davies, D.R. (登録日: 2019-08-01, 公開日: 2020-09-23, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.05 Å)