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Purity: ≥98%
GNE-140 racemate is a novel and potent lactate dehydrogenase (LDHA) inhibitor which is a racemic mixture of (R)-GNE-140 and (S)-GNE-140. 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.
| ln Vitro |
The "Warburg effect" refers to the increased glycolysis that causes greater glucose consumption, which separates cancerous cells from healthy cells. The primary enzyme thought to be in charge of converting pyruvate into lactate is lactate dehydrogenase A (LDHA), a crucial glycolytic enzyme and a marker of aggressive cancer [1].
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| References |
Nat Chem Biol.2016 Oct;12(10):779-86;ACS Med Chem Lett.2016 Aug 26;7(10):896-901.
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| Molecular Formula |
C25H23CLN2O3S2
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|---|---|
| Molecular Weight |
499.044722795486
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| CAS # |
1809794-70-4
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| Related CAS # |
(R)-GNE-140;2003234-63-5;(S)-GNE-140;2003234-64-6
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| SMILES |
O=C1C(SC2=CC=CC=C2Cl)=C(O)CC(C3=CSC=C3)(C4=CC=C(N5CCOCC5)C=C4)N1
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| InChi Key |
SUFXXEIVBZJOAP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H23ClN2O3S2/c26-20-3-1-2-4-22(20)33-23-21(29)15-25(27-24(23)30,18-9-14-32-16-18)17-5-7-19(8-6-17)28-10-12-31-13-11-28/h1-9,14,16,29H,10-13,15H2,(H,27,30)
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| Chemical Name |
3-((2-Chlorophenyl)thio)-4-hydroxy-6-(4-morpholinophenyl)-6-(thiophen-3-yl)-5,6-dihydropyridin-2(1H)-one
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| Synonyms |
GNE-140 racemic; GNE-140; GNE 140; GNE140.
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0038 mL | 10.0192 mL | 20.0385 mL | |
| 5 mM | 0.4008 mL | 2.0038 mL | 4.0077 mL | |
| 10 mM | 0.2004 mL | 1.0019 mL | 2.0038 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Overlay of previously disclosed X-ray structures of LDHA/diketone-containing inhibitor complexes 4QO7 (cyan) and 4QO8 (white).Hydrogen bonds from 4QO7 are shown as yellow dashed lines.ACS Med Chem Lett.2016 Aug 26;7(10):896-901. |
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 Compound9(cyan) cocrystallized with LDHA (white) [PDB: 5IXS]. The NADH cofactor is shown in green sticks, the crystallographic water as a red sphere, and hydrogen bonds are yellow dashed lines.ACS Med Chem Lett.2016 Aug 26;7(10):896-901. |
 Overlay of the crystal structures29(white) [PDB: 4ZVV] and30(cyan) [PDB: 5IXY] bound to LDHA. Hydrogen bonds are shown as yellow dashed lines.ACS Med Chem Lett.2016 Aug 26;7(10):896-901. |
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