4ZVV

Lactate dehydrogenase A in complex with a trisubstituted piperidine-2,4-dione inhibitor GNE-140

4ZVV の概要

• エントリーDOI: 10.2210/pdb4zvv/pdb
• 分子名称: L-lactate dehydrogenase A chain, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: oxidoreductase inhibitor complex, ldha-g02792140, oxidoreductase-oxidoreductase inhibitor complex, 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: 152261.01

構造登録者

Li, Y.,Chen, Z.,Eigenbrot, C. (登録日: 2015-05-18, 公開日: 2016-05-18, 最終更新日: 2023-09-27)

主引用文献

Boudreau, A.,Purkey, H.E.,Hitz, A.,Robarge, K.,Peterson, D.,Labadie, S.,Kwong, M.,Hong, R.,Gao, M.,Del Nagro, C.,Pusapati, R.,Ma, S.,Salphati, L.,Pang, J.,Zhou, A.,Lai, T.,Li, Y.,Chen, Z.,Wei, B.,Yen, I.,Sideris, S.,McCleland, M.,Firestein, R.,Corson, L.,Vanderbilt, A.,Williams, S.,Daemen, A.,Belvin, M.,Eigenbrot, C.,Jackson, P.K.,Malek, S.,Hatzivassiliou, G.,Sampath, D.,Evangelista, M.,O'Brien, T.
Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
Nat.Chem.Biol., 12:779-786, 2016

PubMed Abstract: Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.

PubMed: 27479743
DOI: 10.1038/nchembio.2143

実験手法

X-RAY DIFFRACTION (2.2 Å)