8BSK

Human GLS in complex with compound 3

Summary for 8BSK

• Entry DOI: 10.2210/pdb8bsk/pdb
• Descriptor: 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)
• Functional Keywords: hydrolase, glutaminase, thiadiazole, pyridazine, inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36077.86

Authors

Debreczeni, J.E. (deposition date: 2022-11-25, release date: 2023-01-18, Last modification date: 2024-06-19)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)