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].

• 动物研究
  剂量	Mice: 5 mg/kg - 200 mg/kg[1] (p.o.); 1 mg/kg[1] (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Dose 1 mg/kg (i.v.) 5 mg/kg (p.o.) Administration i.v. p.o. F 70% (p.o.) T1/2 1.0 h (i.v.) AUC 1.5 μM·h (i.v.) 5.1 μM·h (p.o.) CLp 21.1 ml/min/kg (i.v.) Cmax 2.5 μM (i.v.) 1.7 μM (p.o.) Vss 1.4 L/kg (i.v.)