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ABSTRACT
Introduction
Kidney-type glutaminase (GLS1), a key enzyme controlling the hydrolysis of glutamine to glutamate to resolve the ‘glutamine addiction’ of cancer cells, has been shown to play a central role in supporting cancer growth and proliferation. Therefore, the inhibition of GLS1 as a novel cancer treating strategy is of great interest.
Areas covered
This review covers recent patents (2019-present) involving GLS1 inhibitors, which are mostly focused on their chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications.
Expert opinion
Currently, despite significant efforts, the search for potent GLS1 inhibitors has not resulted in the development of compounds for therapeutic applications. Most recent patents and literature focus on GLS1 inhibitors IPN60090 and DRP104, which have entered clinical trials. While other patent disclosures during this period have not generated any drug candidates, the clinical update will inform the potential of these inhibitors as promising therapeutic agents either as single or as combination interventions.
Article highlights
Comprehensive analysis of patents and literature from reputed institutions, such as The Johns Hopkins University, JacoBio Pharmaceuticals Co., Ltd., Pittsburgh and Cornell, and China Pharmaceutical University.
Review of GLS1 inhibitors (2019–2022) based on chemical structures and the biological activities of the representative compounds.
Combinations of GLS1 inhibitors and other drugs.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author Contributions Statement
J Bian, D Wang, X Li, G Gong, Y Lu, Z Guo are responsible for writing the whole manuscript. Z Li and J Bian are in charge of checking and revision. R Chen and H Huang contributed much work to create figures.
Abbreviations
| abbreviation | = | full name |
| GLS | = | glutaminase |
| the TCA cycle | = | the tricarboxylic acid cycle |
| ATP | = | Adenosine Triphosphate |
| ROS | = | Reactive oxygen species |
| NADPH | = | nicotinamide adenine dinucleotide |
| PDG-PET | = | Fluorodeoxyglucose position emission computed tomography |
| GLS1 | = | kidney-type glutaminase |
| GLS2 | = | liver-type glutaminase |
| KGA | = | kidney glutaminase |
| GAC | = | glutaminase C |
| LGA | = | Liver glutaminase |
| PH | = | Pulmonary Hypertension |
| CTLA-4 | = | Cytotoxic T-Lymphocyte Antigen 4 |
| PD1 | = | programmed death-1 |
| PDL1 | = | programmed death ligand |
| DON | = | 6-diazo-5-oxo-L-norleucine |
| BPTES | = | Bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethylsulfide |
| HLM | = | Human liver microsomes |