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(R)-GNE-140

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Chemical Structure| 2003234-63-5 同义名 : -
CAS号 : 2003234-63-5
货号 : A932685
分子式 : C25H23ClN2O3S2
纯度 : 99%+
分子量 : 499.045
MDL号 : MFCD31560470
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(100.19 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
描述 In the lactate dehydrogenase (LDH) family, Lactate dehydrogenase A (LDHA) is the enzyme that catalyzes the conversion of L-lactate and NAD to pyruvate and NADH in the final step of anaerobic glycolysis. Another isoform, Lactate dehydrogenase B (LDHB) catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+ in a post-glycolysis process. As altered glycolytic metabolism is a feature of cancer cells, inhibition of LDHA and LDHB, thus reducing glycolysis was assumed to have anti-tumor potential. R）-GNE-140 is an LDH inhibitor. Based on enzymatic assays, the inhibitory IC50 values of (R)-GNE-140 against LDHA and LDHB are 3 nM and 5 nM, respectively. Results of a lactate production assay in pancreatic MiaPaca2 cell line shows that (R)-GNE-140 inhibited lactate production with the IC­50 of 0.67 μM[2]. In an experiment to determine the IC50s of (R)-GNE-140 across a panel of pancreatic cell lines, it was reported that the 4 cell lines of MiaPaca2, KP2, PSN1 and Hup-T3 are sensitive to (R)-GNE-140 with IC50s below 5 μM. When MiaPaca-2 cells were incubated with 2 μM (R)-GNE-140 for the 1 - 5 days and then assessed for levels of active caspase-3 or sub-2N content, levels of active caspase-3 increased within 1 - 2 d and peaked at around days 2 - 3, while obvious increase in cell death (appearance of cells with a DNA content <2N) was first detected at day 3[3]. In xenograft studies, (R)-GNE-140 was administrated to MiaPaca-2-tumor-bearing mice twice daily at 100, 200, and 400 mg/kg for a total of 7 days. A dose-dependent significant reduction in lactate levels and a corresponding increase in both pyruvate and glycerol-3-phosphate levels was observed within 1h of the last GNE-140 dose but not 6h after the last dose, suggesting rapid clearance of GNE-140 in vivo. Consequently, tumor-bearing mice treated for 21 d with twice daily administration of 100, 200 and 400 mg/kg GNE-140 showed no tumor growth inhibition when compared to vehicle control animals[3].
作用机制 X-ray structure assay revealed that GNE-140 bound to LDHA by forming hydrogen bonds in the active site adjacent to NADH[3].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.00mL

0.40mL

0.20mL

10.02mL

2.00mL

1.00mL

20.04mL

4.01mL

2.00mL
参考文献

[1]Purkey HE, Robarge K, et al. Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice. ACS Med Chem Lett. 2016 Aug 26;7(10):896-901. eCollection 2016 Oct 13.

[2]Purkey HE, Robarge K, Chen J, Chen Z, Corson LB, Ding CZ, DiPasquale AG, Dragovich PS, Eigenbrot C, Evangelista M, Fauber BP, Gao Z, Ge H, Hitz A, Ho Q, Labadie SS, Lai KW, Liu W, Liu Y, Li C, Ma S, Malek S, O'Brien T, Pang J, Peterson D, Salphati L, Sideris S, Ultsch M, Wei B, Yen I, Yue Q, Zhang H, Zhou A. Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice. ACS Med Chem Lett. 2016 Aug 26;7(10):896-901.

[3]Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D, Labadie S, Kwong M, Hong R, Gao M, Del Nagro C, Pusapati R, Ma S, Salphati L, Pang J, Zhou A, Lai T, Li Y, Chen Z, Wei B, Yen I, Sideris S, McCleland M, Firestein R, Corson L, Vanderbilt A, Williams S, Daemen A, Belvin M, Eigenbrot C, Jackson PK, Malek S, Hatzivassiliou G, Sampath D, Evangelista M, O'Brien T. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nat Chem Biol. 2016 Oct;12(10):779-86.