GNE-140

GNE-140 is an orally active and selective inhibitor of lactate dehydrogenase (LDH) A, B and C, with IC₅₀ values of 3, 5 and 5 nM against LDHA, LDHB, LDHC, respectively. GNE-140 blocks the conversion of pyruvate to lactate, reduces lactate production and histone lysine lactylation, and inhibits glycolysis. GNE-140 attenuates cardiac hypertrophy, alleviates PM_2.5-induced pulmonary inflammation and fibrosis, blocks MRSA-induced Arg1 expression, regulates metabolites of glycolysis and the pentose phosphate pathway, reduces glucose uptake, increases ROS, and induces cancer cell apoptosis. GNE-140 is applicable to research related to pathological cardiac hypertrophy, pulmonary fibrosis, MRSA infection and pancreatic cancer^[1][2][3][4]. In Vitro:GNE-140 (10 μM; 48 h) reduces intracellular lactate levels, decreases the surface area of neonatal mouse cardiomyocytes, downregulates the expression of cardiac hypertrophy markers, and inhibits multiple histone lysine lactylation modifications, thereby alleviating angiotensin II (Ang II)-induced hypertrophy of neonatal mouse cardiomyocytes (NMCM)^[1].
Pretreatment of mouse RAW264.7 macrophages with GNE-140 (10 μM; 4 h) inhibits PM_2.5-induced glycolysis, histone lactylation, pro-fibrotic gene expression and cytokine secretion, and partially reverses macrophage-mediated epithelial-mesenchymal transition (EMT) in MLE-12 cells^[2].
GNE-140 (6-12 h) inhibits MSM-induced Arg1 mRNA expression in MRSA-infected THP1 cells at 6 h and 12 h post-infection^[3].
GNE-140 (6-12 h) blocks MSM-induced Arg1 protein expression in THP1 cells infected with MRSA at 6 h and 12 h post-infection^[3].
GNE-140 (6-72 h) disrupts the glycolysis process and inhibits the proliferation of human pancreatic cancer cell line MIA PaCa-2, with an EC₅₀ of 0.67 μM for lactate production inhibition (6 h) and an IC₅₀ of 0.43 μM for proliferation inhibition (72 h)^[4].
GNE-140 (2 μM; 1-5 d) induces Caspase-3 activation in MIA PaCa-2 cells at 1-2 d, and triggers cell death after 3 d; the occurrence of irreversible cell death requires continuous exposure^[4].
GNE-140 (0-10 μM; 0-48 h) modulates global metabolism in MIA PaCa-2 cells, reduces glucose uptake capacity (IC₅₀ = 0.47 μM, 6 h), increases ROS levels, and redirects glycolytic carbon flux from lactate toward pyruvate, alanine, and the pentose phosphate pathway^[4].
GNE-140 (6-72 h) inhibits the proliferation of 13% of the tested pancreatic cell lines (glycolysis-dependent cell lines) with an IC₅₀ < 5 μM, and disrupts glycolysis in both sensitive and resistant cell lines^[4].
GNE-140 (8-10 d) generates stable clones with over 100-fold drug resistance from MIA PaCa-2 cells, and the metabolism of these clones shifts from glycolysis to OXPHOS-dependent metabolism^[4].
GNE-140 (16-72 h) synergizes with inhibitors of AMPK, S6K or OXPHOS to reduce the viability of MIA PaCa-2 cells, and S6K inhibition prevents metabolic shifts associated with acquired drug resistance^[4]. In Vivo:GNE-140 (5 mg/kg; i.t.; once every other day; 4 weeks) reduces PM_2.5-induced pulmonary inflammation and fibrosis in male C57BL/6 J mice by inhibiting glycolysis and subsequent histone lactylation^[2].
GNE-140 (100-400 mg/kg; p.o.; BID; 7-21 days) transiently modulates glycolytic metabolites in MIA PaCa-2 xenografts in a dose-dependent manner within 1 hour of administration, but does not inhibit tumor growth in in vivo over 21 days due to rapid clearance^[4].