当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Finlay MRV,Anderton M,Bailey A,Boyd S,Brookfield J,Cairnduff C,Charles M,Cheasty A,Critchlow SE,Culshaw J,Ekwuru T,Hollingsworth I,Jones N,Leroux F,Littleson M,McCarron H,McKelvie J,Mooney L,Nissink JWM,Perkins D,

doi

10.1021/acs.jmedchem.9b00260

subject

Has Abstract

pub_date

2019-07-25 00:00:00

pages

6540-6560

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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