5W8J

Crystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 29

5W8J の概要

• エントリーDOI: 10.2210/pdb5w8j/pdb
• 分子名称: 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, MALONIC ACID, ... (6 entities in total)
• 機能のキーワード: oxidoreductase, oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P00338
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 150988.70

構造登録者

Lukacs, C.M.,Moulin, A. (登録日: 2017-06-21, 公開日: 2018-01-17, 最終更新日: 2024-04-03)

主引用文献

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

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: 29120638
DOI: 10.1021/acs.jmedchem.7b00941

実験手法

X-RAY DIFFRACTION (1.55 Å)