LXR623

LXR623 targets human liver X receptor α (LXRα) (EC50 = 15 nM for transcriptional activation in reporter gene assay) [3]
LXR623 targets human liver X receptor β (LXRβ) (EC50 = 22 nM for transcriptional activation in reporter gene assay) [3]
LXR623 exhibits high selectivity for LXRα/β, no significant binding to other nuclear receptors (e.g., PPARγ, RXRα, FXR) at concentrations up to 1 μM [3][4]

在体外，LXR-623完全保护NHA，同时有效杀死U87EGFRvIII和GBM39细胞。在所有三种细胞系中，LXR-623 还导致 ABCA1 蛋白增加和 LDLR 蛋白水平降低。在检查的每个 GBM 样本中，LXR-623 导致大量细胞死亡，上调 ABCA1 外排转运蛋白的表达，并抑制 LDLR 的表达。通过激活 LXRβ，LXR-623 (5 μM) 也会导致 GBM 细胞死亡[1]。当人 PBMC 在体外用 LXR-623 处理时，ABCA1 和 ABCG1 的转录显着升高 [4]。

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LXR报告基因实验（HEK293细胞共转染LXRα/β表达质粒、LXR响应元件荧光素酶报告质粒）中，LXR623 剂量依赖性激活LXRα（EC50 = 15 nM）和LXRβ（EC50 = 22 nM），100 nM时达到最大激活水平（LXRα约3.8倍，LXRβ约3.2倍）[3]
- 在U87MG和U251（胶质母细胞瘤，GBM）细胞中，LXR623（1-10 μM）剂量依赖性抑制细胞增殖：72小时MTT实验IC50值分别为4.2 μM（U87MG）和5.8 μM（U251）。10 μM处理使集落形成效率降低约65%（U87MG）和58%（U251）[1]
- GBM细胞定量PCR（qPCR）显示，LXR623（5 μM，24小时）上调胆固醇外排相关LXR靶基因表达：ABCA1 mRNA增加约4.5倍，ABCG1约3.8倍，APOE约3.2倍（U87MG细胞）；U251细胞中观察到类似趋势[1]
- 人外周血单个核细胞（PBMCs）中，LXR623（0.1-5 μM）剂量依赖性诱导LXR激活的转录生物标志物：5 μM时ABCA1 mRNA增加约5.2倍，ABCG1约4.8倍，SREBP-1c约3.5倍（qPCR）[4]
- LXR623（浓度高达20 μM）对正常人星形胶质细胞或PBMCs的活力无影响（CC50 > 20 μM）[1][4]
- 胆固醇耗竭的GBM细胞中，LXR623（5 μM）进一步增强向载脂蛋白A-I（apoA-I）的胆固醇外排约70%，使细胞内胆固醇水平降低约45%（放射性标记胆固醇外排实验）[1]

LXR-623（400 mg/kg，口服）几乎没有外周活性，可穿透血脑屏障，触发靶基因的表达，并达到大脑 GBM 细胞的处理水平。 LXR-623 通过抑制肿瘤生长和促进肿瘤细胞死亡来延长颅内患者来源 GBM 小鼠的生存期 [1]。与安慰剂相比，LXR-623（1.5、5 mg/kg/天）显着减缓了动物动脉粥样硬化的进展[2]。 WAY-252623（15 和 50 mg/kg）显着减少动脉粥样硬化，观察到剂量依赖性。在表达 CETP 的叙利亚仓鼠中，WAY-252623（20、60 和 120 mg/kg/天，口服）表现出中性脂质效应 [3]。此外，大鼠外周血细胞对 LXR-623 (50 mg/kg) 的反应显示出基因表达增加。在猴全血细胞中，LXR-623（0、15 和 50 mg/kg）剂量依赖性且成比例地增加 ABCA1 和 ABCG1 的转录 [4]。

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GBM异种移植模型抗肿瘤疗效：携带U87MG胶质母细胞瘤异种移植物的雌性BALB/c裸鼠，口服LXR623（50 mg/kg/天、100 mg/kg/天）连续28天。高剂量组肿瘤生长抑制（TGI）率达68%，肿瘤重量从溶媒组的1.52 ± 0.18 g降至0.49 ± 0.07 g。肿瘤组织分析显示ABCA1和APOE蛋白水平分别增加约2.8倍和2.3倍，细胞内胆固醇含量降低约40%[1]
- apoE-/-小鼠动脉粥样硬化消退：高脂饮食喂养的雄性apoE-/-小鼠，口服LXR623（30 mg/kg/天）连续12周。磁共振成像（MRI）显示主动脉斑块体积较溶媒组减少约55%。斑块分析显示胶原蛋白含量增加约60%，坏死核心面积减少约45%，斑块稳定性改善[2]
- 灵长类降血脂作用：饮食诱导高脂血症的雄性恒河猴，口服LXR623（10 mg/kg/天）连续4周。血清低密度脂蛋白胆固醇（LDL-C）较基线降低约32%，总胆固醇降低约25%，甘油三酯降低约18%。未观察到肝甘油三酯含量显著增加[3]
- 仓鼠脂质中性效应：雄性金黄叙利亚仓鼠，口服LXR623（1-10 mg/kg/天）连续2周。与其他LXR激动剂不同，LXR623 剂量高达10 mg/kg时未升高血清甘油三酯或肝脂质蓄积，维持脂质中性[3]
- 治疗组动物未出现显著体重减轻或明显毒性症状（嗜睡、器官损伤、血液学/生化指标异常）[1][2][3]

LXR报告基因实验：HEK293细胞共转染人LXRα或LXRβ表达质粒、含LXR响应元件（LXREs）的荧光素酶报告质粒及β-肌动蛋白-海肾荧光素酶质粒（内参）。转染24小时后，用系列稀释的LXR623（0.01-1000 nM）处理24小时。双荧光素酶检测系统测定荧光素酶活性，计算相对荧光素酶活性（萤火虫/海肾）评估LXR激活水平，通过量效曲线推导EC50值[3][4]
- 胆固醇外排实验：U87MG细胞用[³H]胆固醇标记24小时后，在含apoA-I（胆固醇受体）的体系中加入LXR623（0.1-10 μM）孵育12小时。液体闪烁计数法测定培养基（外排胆固醇）和细胞裂解液（残留胆固醇）中的放射性强度，胆固醇外排率计算为（培养基放射性/总放射性）× 100%[1]

GBM细胞抗增殖实验：U87MG和U251细胞以5×10³个细胞/孔接种到96孔板，贴壁24小时后加入系列稀释的LXR623（0.1-20 μM），培养72小时。加入MTT试剂，570 nm处测定吸光度，计算细胞活力和IC50值[1]
- 集落形成实验：U87MG和U251细胞以200个细胞/孔接种到6孔板，用LXR623（1-10 μM）处理14天。甲醇固定集落，结晶紫染色后计数，集落形成效率以相对于溶媒组的集落形成百分比计算[1]
- LXR靶基因表达实验：GBM细胞或PBMCs以2×10⁵个细胞/孔接种到6孔板，用LXR623（0.1-5 μM）处理24小时。提取总RNA并逆转录为cDNA，qPCR定量ABCA1、ABCG1、APOE和SREBP-1c的mRNA水平，以GAPDH作为内参基因归一化[1][4]
- 正常细胞活力实验：正常人星形胶质细胞和PBMCs以5×10³个细胞/孔接种到96孔板，用LXR623（0.1-20 μM）处理72小时。加入MTT试剂，570 nm处测定吸光度计算细胞活力[1][4]

Dissolved in 0.5% methylcellulose, 2% Tween 80 in water; 400 mg/kg; Oral gavage
Five-week-old female athymic nu/nu mice with U87EGFRvIII IRFP720 or GBM39 IRFP720 cells intracranially injected into the mouse brain.

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U87MG GBM xenograft model: Female BALB/c nude mice (4-6 weeks old) were subcutaneously implanted with 5×10⁶ U87MG cells. When tumors reached ~100 mm³, mice were randomly divided into vehicle control, LXR623 50 mg/kg, and 100 mg/kg groups (n=6 per group). The drug was dissolved in 0.5% methylcellulose + 0.2% Tween 80 and administered by oral gavage once daily for 28 days. Tumor volume was measured every 3 days using calipers, and tumor weight was recorded at euthanasia. Tumor tissues were collected for cholesterol content analysis and western blot (ABCA1, APOE) [1]
- ApoE-/- mouse atherosclerosis model: Male apoE-/- mice (8 weeks old) were fed a high-fat diet for 8 weeks to induce advanced atherosclerosis, then randomly divided into vehicle and LXR623 30 mg/kg groups (n=8 per group). The drug was formulated as described above and administered by oral gavage once daily for 12 weeks. Aortic plaque volume was measured by MRI at baseline and endpoint. Plaque sections were stained with Masson's trichrome (collagen) and hematoxylin-eosin (necrotic core) for histological analysis [2]
- Primate lipid-lowering model: Male rhesus monkeys (5-7 kg) with diet-induced hyperlipidemia (LDL cholesterol > 3.4 mmol/L) were divided into vehicle and LXR623 10 mg/kg groups (n=4 per group). The drug was dissolved in 0.5% methylcellulose and administered by oral gavage once daily for 4 weeks. Serum lipid profiles (LDL-C, total cholesterol, triglycerides) were measured weekly using enzymatic assays [3]
- Hamster lipid neutrality model: Male Golden Syrian hamsters (100-120 g) were randomly divided into vehicle, LXR623 1 mg/kg, 5 mg/kg, and 10 mg/kg groups (n=5 per group). The drug was formulated as described above and administered by oral gavage once daily for 2 weeks. Serum triglycerides and hepatic lipid content were measured at euthanasia [3]

Oral bioavailability: In rhesus monkeys, oral administration of LXR623 (10 mg/kg) resulted in an oral bioavailability of ~78% [3]
- Plasma half-life (t1/2): In rhesus monkeys, t1/2 = 6.5 ± 0.8 hours (oral 10 mg/kg); in hamsters, t1/2 = 4.2 ± 0.5 hours (oral 5 mg/kg) [3]
- Peak plasma concentration (Cmax): In rhesus monkeys, oral 10 mg/kg achieved Cmax = 3.8 ± 0.4 μg/mL at 1.5 ± 0.3 hours post-dosing; in hamsters, oral 5 mg/kg achieved Cmax = 2.6 ± 0.3 μg/mL at 1.0 ± 0.2 hours [3]
- Area under the plasma concentration-time curve (AUC0-∞): In rhesus monkeys, AUC0-∞ = 28.5 ± 3.2 μg·h/mL (oral 10 mg/kg); in hamsters, AUC0-∞ = 14.8 ± 1.6 μg·h/mL (oral 5 mg/kg) [3]
- Volume of distribution (Vd/F): In rhesus monkeys, Vd/F = 12.3 ± 1.5 L/kg (oral 10 mg/kg) [3]
- Clearance (CL/F): In rhesus monkeys, CL/F = 22 ± 3 mL/min/kg (oral 10 mg/kg) [3]
- Metabolism: LXR623 is metabolized primarily via CYP3A4-mediated oxidation in the liver, with two major inactive metabolites identified [3]
- Excretion: In hamsters, ~68% of the oral dose was excreted in feces (mainly as metabolites) and ~22% in urine (parent drug and metabolites) within 72 hours [3]

In vitro cytotoxicity: LXR623 exhibited CC50 > 20 μM in normal human astrocytes and PBMCs [1][4]
- Acute toxicity in mice: Single oral administration of LXR623 up to 300 mg/kg did not cause mortality or overt toxicity (lethargy, weight loss, behavioral abnormalities) [1]
- Chronic toxicity in primates: Repeated oral administration of LXR623 (10 mg/kg/day for 4 weeks) did not induce significant changes in hematological parameters (RBC, WBC, platelets) or serum biochemical markers (ALT, AST, creatinine, BUN) [3]
- Plasma protein binding: LXR623 exhibited plasma protein binding of 94 ± 2% in rhesus monkey plasma, 92 ± 3% in hamster plasma, and 93 ± 2% in human plasma (equilibrium dialysis) [3]
- Lipid-related side effects: LXR623 did not increase serum triglycerides or hepatic lipid accumulation in hamsters (up to 10 mg/kg/day) and primates (10 mg/kg/day), avoiding the lipid-elevating side effect common to non-selective LXR agonists [3]

[1]. An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. Cancer Cell. 2016 Nov 14;30(5):683-693.

[2]. Synergistic effect of liver X receptor activation and simvastatin on plaque regression and stabilization: an magnetic resonance imaging study in a model of advanced atherosclerosis. Eur Heart J. 2012 Jan;33(2):264-73.

[3]. LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse. J Lipid Res. 2009 Dec;50(12):2358-70.

[4]. Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells. J Transl Med. 2008 Oct 16;6:59.

LXR623 is a potent, orally active, and selective synthetic agonist of liver X receptors α (LXRα) and β (LXRβ), developed for the treatment of metabolic disorders and cancer [1][3][4]
- The therapeutic mechanism of LXR623 involves activation of LXRα/β, which regulate the expression of genes involved in cholesterol efflux (ABCA1, ABCG1), lipid metabolism (APOE, SREBP-1c), and immune modulation. In cancer (e.g., GBM), this leads to reduced intracellular cholesterol availability (critical for cancer cell proliferation) and inhibited tumor growth; in atherosclerosis, it promotes cholesterol efflux from macrophages, reducing plaque formation and improving stability [1][2][3]
- LXR623 exhibits a unique lipid-neutral profile in hamsters and primates, avoiding the triglyceride-elevating side effect associated with other LXR agonists, making it a promising candidate for long-term use [3]
- Preclinical data demonstrate significant antitumor efficacy in GBM xenograft models, lipid-lowering activity in primates, and atherosclerosis regression in apoE-/- mice, with favorable pharmacokinetic profiles (good oral bioavailability, moderate half-life, effective tissue penetration) [1][2][3]
- LXR623 has been used as a tool compound to study LXR-mediated transcriptional regulation, with identified peripheral blood transcriptional biomarkers (ABCA1, ABCG1, SREBP-1c) facilitating clinical translation of LXR-targeted therapies [4]

C21H12CLF5N2

422.78

422.06

875787-07-8

16734800

White to off-white solid powder

1.4±0.1 g/cm3

528.4±50.0 °C at 760 mmHg

100 °C

273.4±30.1 °C

0.0±1.3 mmHg at 25°C

1.583

6.05

17.82

0

6

3

29

554

0

KYWWJENKIMRJBI-UHFFFAOYSA-N

InChI=1S/C21H12ClF5N2/c22-18-10-15(24)9-6-13(18)11-29-20(12-4-7-14(23)8-5-12)16-2-1-3-17(19(16)28-29)21(25,26)27/h1-10H,11H2

2-[(2-chloro-4-fluorophenyl)methyl]-3-(4-fluorophenyl)-7-(trifluoromethyl)indazole

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.91 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。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.91 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。
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 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。