| 规格 | 价格 | 库存 | 数量 |
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| 10 mM * 1 mL in DMSO |
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| 靶点 |
LDHA (IC50 = 3 nM); LDHB (IC50 = 5 nM)
At a dose of 5 μM, (R)-GNE-140 demonstrated cell proliferation in 37 out of 347 pancreatic lineages that were evaluated. With an IC50 of 0.8 μM, (R)-GNE-140 inhibits two chondroma (bone) hexane lines expressing IDH1 dimming [1]. (R)-GNE-140 proved to possess the optimal combination of strong enzymatic and MiaPaca2 cellular potency, moderate permeability, and reduced plasma protein binding compared to other potent compounds in this series. |
|---|---|
| 体外研究 (In Vitro) |
在 5 μM 剂量下，(R)-GNE-140 在所评估的 347 个胰腺谱系中的 37 个中显示出细胞增殖。 (R)-GNE-140 抑制两种表达 IDH1 的软骨瘤（骨）己烷系，IC50 为 0.8 μM [1]。
与该系列中的其他强效化合物相比，(R)-GNE-140被证明具有强酶和MiaAca2细胞效力、中等渗透性和降低血浆蛋白结合的最佳组合。 R-GNE-140 在MiaPaca2胰腺癌细胞系中显示出强大的细胞活性，抑制乳酸产生的IC₅₀为 0.67 µM。[1] 在包含347种癌细胞系的广泛筛选中，R-GNE-140 在5 µM的效力阈值下，抑制了37种细胞系（11%）的增殖。两个IDH1突变型软骨肉瘤细胞系对其特别敏感，IC₅₀为 0.8 µM。[1] |
| 体内研究 (In Vivo) |
在小鼠中，(R)-GNE-140 (5 mg/kg) 表现出高生物利用度。在之前的枪模拟中，(R)-GNE-140 显示暴露量增加为 50 至 200 mg/kg。
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| 酶活实验 |
体外药物治疗实验。[1]
所有细胞系均来自我们的内部组织培养细胞库（原始来源为ATCC）。通过短串联重复序列（STR）鉴定品系，并在重新扩增时进行基因分型。将细胞维持在补充有10%FBS的RPMI 1640培养基中。使用RPMI、5%FBS、100微克/毫升青霉素和100单位/毫升链霉素在384孔板中以最佳接种密度接种细胞。为每个细胞系建立最佳接种密度，以便在测定结束时达到75-80%的汇合。第二天，使用6pt剂量滴定方案用化合物29处理细胞。72小时后，使用CellTiter-Glo®发光细胞活力测定法评估细胞活力。使用四参数logistic曲线拟合计算绝对抑制浓度（IC）值。 使用生化分析法测定化合物对LDHA和LDHB的酶抑制活性。将重组人LDHA或LDHB蛋白与测试化合物、底物NADH和丙酮酸（用于正向反应）一起孵育。通过监测340 nm处吸光度的降低（对应NADH氧化为NAD⁺）来跟踪反应进程。根据剂量反应曲线计算IC₅₀值。实验至少进行两次独立运行，结果报告为几何平均值。[1] |
| 细胞实验 |
GNE-140表型LDHA/B在LS174T和B16细胞系中的双重遗传破坏处理[2]
最近，Boudreau等人证明了GNE-140（一种特定的LDHA和LDHB抑制剂）在高度糖酵解的胰腺癌症细胞系（如MiaPaca2）中引起生长停滞的能力。因此，我们很好奇这种抑制剂是否能立即重新激活OXPHOS，并维持WT LS174T和B16细胞系的生存能力和生长。我们用不同浓度的GNE-140处理WT和LDHA/B-DKO细胞，结果显示，10μm的浓度（已知会破坏LDHA和B活性）降低了WT的生长，但没有降低本文报道的两种LDHA/B-DKO细胞系的生长。该长期实验（9至12天）证明了在所用浓度下该化合物没有脱靶作用。此外，我们分析了海马生物分析仪对野生型细胞进行短期GNE-140处理的代谢后果。如图6所示，8，用10μm GNE-140处理E–H，1小时足以表型观察LDHA/B-DKO细胞在抑制糖酵解和OXPHOS再激活方面的作用。因此，DLHA/B-DKO细胞的生长表型不是由遗传破坏的两个步骤中的长期生长选择引起的。这一发现基于遗传和LDHA和LDHB的特异性药理学破坏，有力地证明，在正常缺氧条件下，Warburg效应对体外肿瘤生长是可有可无的。 使用MiaPaca2细胞系的乳酸产生实验评估细胞活性。培养细胞并用测试化合物的系列稀释液处理。孵育一段时间后，对培养上清液中的乳酸水平进行定量（通常使用比色法或酶学检测方法）。确定抑制50%乳酸产生的化合物浓度（IC₅₀）。实验至少进行两次独立运行，结果报告为几何平均值。[1] 通过癌细胞系面板评估抗增殖活性。用R-GNE-140（例如，5 µM）处理细胞，并在规定时间（例如，72-96小时）后使用CellTiter-Glo等方法测量细胞活力/增殖。计算敏感细胞系的IC₅₀值。[1] |
| 动物实验 |
Mouse Pharmacokinetics Study [1]
The pharmacokinetics of compound 29 ((R)-GNE-140) was evaluated following a single intravenous bolus (IV) dose of 1.0 mg/kg and oral administration (PO) of solution/amorphous suspension at a dose of 5 mg/kg in female CD-1 mice (N=3). The vehicle used for IV administration was 10/50/40 EtOH/PEG400/50mM citrate pH3 (v/v, 10/50/40), and for PO, 0.5% methycellulose:0.2% Tween in water (MCT). Blood samples for the IV dose group were collected at 0.033, 0.25, 1, 2, 4, 6 hours post dose. Blood samples for PO dose groups were collected at 0.25, 0.5, 1, 2, 4, and 6 hours post dose. For the high dose oral PK study at 50, 100, and 200 mg/kg, blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, and 8 hours post dose. Blood samples were centrifuged within 29 minutes of collection, and plasma was harvested. Plasma samples were stored at approximately –70°C until the analysis of the compound concentration by a liquid chromatography/tandem mass spectrometry (LCMS/MS) method. PK parameters were determined by non-compartmental methods using WinNonlin In vivo pharmacokinetic studies were conducted in mice. R-GNE-140 was administered via intravenous (IV) injection at a dose of 1 mg/kg and via oral gavage (PO) at doses of 5, 50, 100, and 200 mg/kg. The specific formulation or vehicle used for dosing is not described in the manuscript. Blood samples were collected at various time points post-dose for plasma concentration analysis. [1] |
| 药代性质 (ADME/PK) |
(R)-GNE-140 was stable in liver microsomes with predicted hepatic clearances (Clp) of 3.3, 8.1, and 14 mL/min/kg, based on human, rat, and mouse microsomes, respectively. We carried out in vivo pharmacokinetic experiments in mice with (R)-GNE-140 and were gratified to observe that this compound presented a low Clp, consistent with the predicted hepatic Cl, and also had high bioavailability when dosed orally at 5 mg/kg (Table 5; concentration vs time plots in Figure S2). At higher oral doses, ranging from 50 to 200 mg/kg, (R)-GNE-140 displayed greater exposure (Table 5 and Figure S3), confirming the possibility of (R)-GNE-140 serving as a tool compound for in vivo efficacy studies in mice.[1]
In mouse PK studies, following a 1 mg/kg IV dose, R-GNE-140 had an AUC of 1.5 µM·h, a Cₘₐₓ of 2.5 µM, and a plasma clearance (Cₗ) consistent with the predicted hepatic clearance. [1] Following oral administration, exposure was dose-dependent: 5 mg/kg PO: AUC = 5.1 µM·h, Cₘₐₓ = 1.7 µM; 50 mg/kg PO: AUC = 125 µM·h, Cₘₐₓ = 60.7 µM; 100 mg/kg PO: AUC = 250 µM·h, Cₘₐₓ = 224 µM; 200 mg/kg PO: AUC = 403 µM·h, Cₘₐₓ = 440 µM. [1] R-GNE-140 exhibited high oral bioavailability in mice (implied by the significant exposure after oral dosing, though a precise F% is not calculated in the text). [1] It had low predicted hepatic clearance in microsomes: human (3.3 mL/min/kg), rat (8.1 mL/min/kg), mouse (14 mL/min/kg). [1] The compound showed moderate permeability in the MDCK cell assay. [1] The mouse plasma protein binding was 99.1%. [1] The LogD₇.₄ was measured as 0.6. [1] |
| 参考文献 | |
| 其他信息 |
A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 μM) that also possessed good exposure when dosed orally to mice.[1]
R-GNE-140 (Compound 29) is a trisubstituted hydroxylactam discovered through structure-based design. It features a less acidic hydroxylactam core (pKₐ ~4.1) compared to earlier diketone/dihydropyrone scaffolds, aiming to improve physicochemical properties. [1] It is a pan-LDH inhibitor with low nanomolar potency against both LDHA and LDHB isoforms. [1] It represents the first reported LDHA inhibitor with submicromolar cellular potency (MiaPaca2 IC₅₀ = 0.67 µM) combined with favorable pharmacokinetic properties (low clearance, high oral exposure in mice), making it suitable as an in vivo tool compound. [1] Its mechanism of action involves inhibiting the glycolytic enzyme LDHA, thereby disrupting the conversion of pyruvate to lactate, a critical step in the Warburg effect observed in many cancers. [1] It showed selective anti-proliferative activity in a subset of cancer cell lines, with notable sensitivity in IDH1-mutant chondrosarcoma models, suggesting a potential therapeutic application in metabolically vulnerable tumors. [1] |
| 分子式 |
C25H23CLN2O3S2
|
|---|---|
| 分子量 |
499.0447
|
| 精确质量 |
498.083
|
| 元素分析 |
C, 60.17; H, 4.65; Cl, 7.10; N, 5.61; O, 9.62; S, 12.85
|
| CAS号 |
2003234-63-5
|
| 相关CAS号 |
GNE-140 racemate;1802977-61-2;(S)-GNE-140;2003234-64-6; 1809794-70-4 (racemate)
|
| PubChem CID |
121225870
|
| 外观&性状 |
Light yellow to yellow solid
|
| LogP |
4.8
|
| tPSA |
115Ų
|
| 氢键供体(HBD)数目 |
2
|
| 氢键受体(HBA)数目 |
6
|
| 可旋转键数目(RBC) |
5
|
| 重原子数目 |
33
|
| 分子复杂度/Complexity |
739
|
| 定义原子立体中心数目 |
1
|
| SMILES |
C1COCCN1C2=CC=C(C=C2)[C@]3(CC(=C(C(=O)N3)SC4=CC=CC=C4Cl)O)C5=CSC=C5
|
| InChi Key |
SUFXXEIVBZJOAP-RUZDIDTESA-N
|
| InChi Code |
InChI=1S/C25H23ClN2O3S2/c26-20-3-1-2-4-22(20)33-23-21(29)15-25(27-24(23)30,18-9-14-32-16-18)17-5-7-19(8-6-17)28-10-12-31-13-11-28/h1-9,14,16,29H,10-13,15H2,(H,27,30)/t25-/m1/s1
|
| 化学名 |
(R)-3-((2-Chlorophenyl)thio)-4-hydroxy-6-(4-morpholinophenyl)-6-(thiophen-3-yl)-5,6-dihydropyridin-2(1H)-one
|
| 别名 |
R-GNE-140; (R)-GNE-140; (R)-GNE-140; 2003234-63-5; (R)-3-((2-chlorophenyl)thio)-4-hydroxy-6-(4-morpholinophenyl)-6-(thiophen-3-yl)-5,6-dihydropyridin-2(1H)-one; (2R)-5-(2-chlorophenyl)sulfanyl-4-hydroxy-2-(4-morpholin-4-ylphenyl)-2-thiophen-3-yl-1,3-dihydropyridin-6-one; R-GNE-140; (2~{r})-5-(2-Chlorophenyl)sulfanyl-2-(4-Morpholin-4-Ylphenyl)-4-Oxidanyl-2-Thiophen-3-Yl-1,3-Dihydropyridin-6-One; inhibitor GNE-140; GNE 140; GNE140.
|
| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
DMSO : ≥ 50 mg/mL (~100.19 mM)
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|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (5.01 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: 2.5 mg/mL (5.01 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.5 mg/mL (5.01 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 配方 4 中的溶解度: 2.5 mg/mL (5.01 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0038 mL | 10.0192 mL | 20.0385 mL | |
| 5 mM | 0.4008 mL | 2.0038 mL | 4.0077 mL | |
| 10 mM | 0.2004 mL | 1.0019 mL | 2.0038 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
 Overlay of previously disclosed X-ray structures of LDHA/diketone-containing inhibitor complexes 4QO7 (cyan) and 4QO8 (white).Hydrogen bonds from 4QO7 are shown as yellow dashed lines.ACS Med Chem Lett.2016 Aug 26;7(10):896-901. |
|---|
 Compound9(cyan) cocrystallized with LDHA (white) [PDB: 5IXS]. The NADH cofactor is shown in green sticks, the crystallographic water as a red sphere, and hydrogen bonds are yellow dashed lines.ACS Med Chem Lett.2016 Aug 26;7(10):896-901. |
 Overlay of the crystal structures29(white) [PDB: 4ZVV] and30(cyan) [PDB: 5IXY] bound to LDHA. Hydrogen bonds are shown as yellow dashed lines.ACS Med Chem Lett.2016 Aug 26;7(10):896-901. |
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