8BSK

Human GLS in complex with compound 3

8BSK の概要

• エントリーDOI: 10.2210/pdb8bsk/pdb
• 分子名称: Glutaminase kidney isoform, mitochondrial 65 kDa chain, SULFATE ION, N,N'-[sulfanediylbis(ethane-2,1-diyl-1,3,4-thiadiazole-5,2-diyl)]bis(2-phenylacetamide), ... (4 entities in total)
• 機能のキーワード: hydrolase, glutaminase, thiadiazole, pyridazine, inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36077.86

構造登録者

Debreczeni, J.E. (登録日: 2022-11-25, 公開日: 2023-01-18, 最終更新日: 2024-06-19)

主引用文献

Finlay, M.R.V.,Anderton, M.,Bailey, A.,Boyd, S.,Brookfield, J.,Cairnduff, C.,Charles, M.,Cheasty, A.,Critchlow, S.E.,Culshaw, J.,Ekwuru, T.,Hollingsworth, I.,Jones, N.,Leroux, F.,Littleson, M.,McCarron, H.,McKelvie, J.,Mooney, L.,Nissink, J.W.M.,Perkins, D.,Powell, S.,Quesada, M.J.,Raubo, P.,Sabin, V.,Smith, J.,Smith, P.D.,Stark, A.,Ting, A.,Wang, P.,Wilson, Z.,Winter-Holt, J.J.,Wood, J.M.,Wrigley, G.L.,Yu, G.,Zhang, P.
Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.
J Med Chem, 62:6540-6560, 2019

PubMed Abstract: Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

PubMed: 31199640
DOI: 10.1021/acs.jmedchem.9b00260

実験手法

X-RAY DIFFRACTION (2.1 Å)