(R)-GNE-140 is an orally active lactate dehydrogenase A (LDHA) inhibitor. (R)-GNE-140 exhibits inhibitory activity against both LDHA (IC50=3nM) and LDHB (IC50=5nM), with its (R)-isomer demonstrating higher activity compared to the S-isomer[1-2]. (R)-GNE-140 can reduce intracellular lactate levels while upregulating pyruvate content, thereby affecting the proliferation and survival of glycolysis-dependent cancer cells. (R)-GNE-140 is primarily utilized in cancer-related research[3-4].
In vitro, pretreatment of periodontal ligament stem cells (PDLSCs) and bone marrow stromal cells (BMSCs) with (R)-GNE-140 (10μM) for 12 hours, followed by induction of osteogenic differentiation, (R)-GNE-140 significantly reduced cell proliferation and decreased the expression of osteogenic differentiation proteins[5]. Treatment of thyroid cancer cell lines with (R)-GNE-140 (0.041-30μM) for 72 hours, (R)-GNE-140 caused a dose-dependent decrease in proliferation and viability across all cell lines[6].
In vivo, BALB/c mice inoculated with KRASG12V/MYC tumor cells were treated with low-dose (2.5mg/kg) and high-dose (5mg/kg) (R)-GNE-140 via intragastric administration (once every two days for a total of seven doses). (R)-GNE-140 (5mg/kg) significantly inhibited tumor volume and weight and reduced the expression levels of lactylated proteins (Kla)[7]. In 4T1 breast cancer-bearing BALB/c mice, treatment with (R)-GNE-140 (2.5mg/kg or 5mg/kg) via intragastric administration (once every two days), (R)-GNE-140 significantly reduced tumor growth rates and downregulated histone H4K79 and H4K91 lactylation modifications (H4K79la/H4K91la)[8].
References:
[1] Purkey HE, Robarge K, Chen J, 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.
[2] Gong Y, Ji P, Yang YS, et al. Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets. Cell Metab. 2021 Jan 5;33(1):51-64.e9.
[3] Huang Q, Sun Y, Kuang P, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Modulate the Course of Peritoneal Inflammation Through Metabolic and Epigenetic Regulation. Adv Sci (Weinh). 2025 Nov 26:e08645.
[4] Feng Y, Pathria G, Heynen-Genel S, et al. Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma. Mol Cancer Ther. 2021 May;20(5):816-832.
[5] Yang W, Guo Q, Quan S, et al. Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors. Sci Adv. 2025 Jul 18;11(29):eadw5228.
[6] Frank AR, Li V, Shelton SD, et al. Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid. Cancer Discov. 2023 Aug 4;13(8):1884-1903.
[7] Liu J, Wang J, Wang Z, et al. PGC-1α/LDHA signaling facilitates glycolysis initiation to regulate mechanically induced bone remodeling under inflammatory microenvironment. Bone. 2024 Aug;185:117132.
[8] Liu J, Zhao L, Yan M, et al. H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer. J Exp Clin Cancer Res. 2025 Aug 23;44(1):252.
(R)-GNE-140是一种具有口服活性的乳酸脱氢酶A（LDHA）抑制剂，(R)-GNE-140对LDHA（IC50=3nM）和LDHB（IC50=5nM）的抑制活性均比S型异构体的高[1-2]。(R)-GNE-140能够降低细胞内的乳酸水平，同时上调丙酮酸含量，从而影响糖酵解依赖的癌细胞增殖与存活，(R)-GNE-140主要被用于癌症相关的研究[3-4]。
在体外，(R)-GNE-140（10μM）预处理牙周韧带干细胞（PDLSCs）和骨髓基质细胞（BMSC）12小时，随后诱导细胞成骨分化。(R)-GNE-140显著降低细胞增殖，降低成骨分化蛋白的表达[5]。(R)-GNE-140（0.041-30μM）处理甲状腺癌细胞系72小时，(R)-GNE-140处理在所有细胞系中均引起剂量依赖性的增殖和存活率下降[6]。
在体内，BALB/c小鼠接种KRASG12V/MYC肿瘤细胞后，分别接受低剂量（2.5mg/kg）和高剂量（5mg/kg）的(R)-GNE-140灌胃治疗（每2天一次，共7次）。(R)-GNE-140（5mg/kg）显著抑制肿瘤体积和重量，且降低乳酸化蛋白（Kla）的表达水平[7]。在4T1乳腺癌荷瘤BALB/c小鼠中，(R)-GNE-140（2.5mg/kg或5mg/kg）灌胃治疗（每2天一次）显著降低肿瘤生长速率，并下调组蛋白H4K79和H4K91的乳酸化修饰（H4K79la/H4K91la）[8]。