LDH-IN-1

LDH-IN-1 is a novel pyrazole-based inhibitor of human lactate dehydrogenase (LDH) with IC50s of 32 and 27 nM for LDHA and LDHB, respectively.

Signaling Pathways >> Metabolic Enzyme/Protease >> Lactate Dehydrogenase

Research Areas >> Cancer

IC50: 32 nM (LDHA), 27 nM (LDHB)[1]

LDH-IN-1 exhibits low nM inhibition of both LDHA and LDHB (IC50=32, 27 nM, respectively), submicromolar inhibition of lactate production, and inhibition of lactate in MiaPaCa2 pancreatic cancer and A673 sarcoma cells (IC50=0.517, 0.854μM, respectively). LDH-IN-1 inhibits the growth of MiaPaCa2 pancreatic cancer and A673 sarcoma cells with IC50s of 2.23 and 1.21 μM). Dose−response treatment of MiaPaCa-2 cells with LDH-IN-1 shows effects on cellular proliferation at concentrations as low as 250 nM and with nearly complete arrest of cell growth at 20 μM[1].

LDH-IN-1 shows clearance values that far exceed hepatic blood flow (HBF) in mouse species (90 mL/min/kg), with in vivo clearances of 227 mL/min/kg[1].

A673 and MiaPaCa-2 cellsA673 and MiaPaCa-2 cells are cultured and plated in 1536-well white solid tissue culture plates. A 1536-well pintool dispenser outfitted with 20 nL pins is used to transfer 23 nL of LDH-IN-1 in DMSO to the 1536-well assay plates. After a 48 h incubation at 37°C, 2.5 μL of CellTiter-Glo is dispensed into each well using a BioRAPTR FRD dispenser. Plates are incubated at room temperature for 10 min, transferred to a ViewLux microplate imager, and the ATP-coupled luminescence is measured using a 1 s exposure[1].

Mice[1] Male CD1 mice approximately 6−8 weeks of age and a weight of approximately 20−30 g, are dosed with LDH-IN-1 at 2 mg/ kg (iv) and 50 mg/kg (po). Each cohort had three mice, and plasma is collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24h postdose for iv and 15 min 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h for po. Approximately 0.025 mL of blood is collected via the dorsal metatarsal vein at each time point. Blood samples are then transferred into plastic microcentrifuge tubes containing heparin−Na as anticoagulant. Samples are then centrifuged at 4000g for 5 min at 4 °C to obtain plasma. Plasma samples are then stored in polypropylene tubes, quickly frozen, and kept at −75 °C until analyzed by LC/MS/MS[1].

[1]. Rai G, et al. Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). J Med Chem. 2017 Nov 22;60(22):9184-9204.

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