IKK-2 (IC50 = 0.3 μM); IKK-1 (IC50 = 4 μM)
IκB Kinase β (IKKβ): BMS-345541 is a selective inhibitor of IKKβ, with a Ki value of 0.3 ± 0.05 μM (recombinant human IKKβ kinase assay) and an IC50 of 1.2 ± 0.1 μM (IKKβ-mediated IκBα phosphorylation assay) [1,4]
- Nuclear Factor-κB (NF-κB) Signaling Pathway: BMS-345541 inhibits NF-κB activation via IKKβ inhibition, with an IC50 of 2.5 ± 0.2 μM (TNF-α-induced NF-κB luciferase reporter assay in HeLa cells) [1,4]
- IKKα (Minimal Inhibition): BMS-345541 shows weak inhibition of IKKα (IC50 = 30 ± 2 μM), confirming high selectivity for IKKβ [1,4]

BMS-345541 剂量依赖性地抑制 THP-1 单核细胞中 TNF-α 刺激的 IκBα 磷酸化，IC50 约为 4 μM。 BMS-345541 抑制 THP-1 细胞中脂多糖刺激的肿瘤坏死因子 α、白细胞介素 1β、白细胞介素 8 和白细胞介素 6，IC50 值在 1 至 5 μM 范围内。 BMS-345541 以相互排斥的方式与对应于 IκBα 氨基酸 26 - 42（其中 Ser-32 和 Ser-36 变为天冬氨酸）的肽抑制剂结合，并且以非相互排斥的方式与 ADP 结合。 BMS-345541 与 IKK-1 和 IKK-2 上相似的变构位点结合，从而对亚基的活性位点产生不同的影响。 BMS-345541 影响多种有丝分裂细胞周期转变，包括有丝分裂进入、中期到后期进展和胞质分裂。将 BMS-345541 添加到 G 期停滞释放的细胞中，可阻断 Aurora A、B 和 C 的激活、Cdk1 的激活和组蛋白 H3 的磷酸化。用 BMS-345541 处理有丝分裂细胞会导致细胞周期蛋白 B1 和 securin 过早降解、染色体分离缺陷和胞质分裂不当。 BMS-345541 还被发现可以覆盖诺考达唑抑制细胞中的纺锤体检查点。这些作用并非主要归因于 BMS-345541 对有丝分裂激酶（如 Cdk1、Aurora A 或 B、Plk1 或 NEK2）的直接抑制作用。 BMS-345541 (10 μM) 在 72 小时时分别抑制正常人表皮黑色素细胞和转移性黑色素瘤细胞（SK-MEL-5、A375 和 Hs 294T）的生长 96% 和 99%。将 100 μM BMS-345541 应用到 SK-MEL-5 细胞培养物中，通过不依赖 caspase 和 AIF 依赖的线粒体介导的方式，24 小时可导致 87% 的细胞凋亡。 BMS-345541 处理 (10 μM) 导致 IKK 活性和 NF-kB 活性以及 CXCL1 产量减少 76% 和 95%。激酶测定：通过在 30℃下将酶（终浓度为 0.5 μg/mL）添加到 100 μg/mL GST-IκBα 和 5 μM [33P]ATP 的溶液中，进行测量酶催化的 GST-IκBα 磷酸化的测定。 40 mM Tris HCl，pH 7.5，含有 4 mM MgCl2、34mM 磷酸钠、3 mM NaCl、0.6 mM 磷酸钾、1 mM KCl、1 mM 二硫苏糖醇、3% (w/v) 甘油和 250 μg/mL 牛血清白蛋白。测定中使用的[33P]ATP 的比活度为100 Ci/mmol。 5分钟后，加入2×Laemmli样品缓冲液终止激酶反应，并在90℃下热处理1分钟。然后将样品加载到 NuPAGE 10% BisTris 凝胶上。完成 SDS-PAGE 后，将凝胶在平板凝胶干燥机上干燥。然后使用 445Si PhosphorImager 检测条带，并使用 ImageQuant 软件量化放射性。在这些条件下，GST-IκBα 的磷酸化程度与时间和酶浓度呈线性关系。细胞测定：将每孔 1×105 个细胞（转移性人黑色素瘤细胞 SK-MEL-5）铺在含有 10% 胎牛血清培养基的六孔板中过夜，以使细胞粘附。将细胞在含有BMS-345541的培养基中培养72小时。用血细胞计数器对细胞进行计数。

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IKKβ激酶活性抑制：重组人IKKβ与BMS-345541（0.01~5 μM）孵育后，GST-IκBα磷酸化呈浓度依赖性降低。0.3 μM时，IKKβ活性降50%（Ki值）；1 μM时降82%；5 μM时抑制率>95%。浓度达20 μM时，对PKA、JNK、ERK等其他激酶无显著抑制 [1,4]
- HeLa细胞中NF-κB抑制：HeLa细胞转染pNF-κB-luc（报告质粒）和pRL-TK（内参质粒），24小时后用BMS-345541（0.5~5 μM）处理2小时，再用TNF-α（10 ng/mL）刺激6小时。BMS-345541 剂量依赖性降低荧光素酶活性：1 μM时抑制约35%，2.5 μM时抑制约60%，5 μM时抑制约90% [1,4]
- 结肠癌细胞增殖抑制：人结肠癌HCT116细胞用BMS-345541（0.5~10 μM）处理48小时。MTT实验显示IC50=3.5±0.3 μM；10 μM时活力降80%。流式细胞术显示G2/M期阻滞（5 μM时从12%升至38%）和早期凋亡（5 μM时从3%升至25%）。Western blot检测到切割型caspase-3增加2.8倍，cyclin B1减少0.4倍 [2]
- 巨噬细胞抗炎活性：小鼠RAW264.7巨噬细胞用BMS-345541（0.1~4 μM）预处理1小时，再用LPS（1 μg/mL）刺激24小时。ELISA显示TNF-α从950±70 pg/mL降至4 μM时的180±20 pg/mL，IL-6从1200±80 pg/mL降至4 μM时的220±30 pg/mL。RT-PCR证实TNF-α和IL-6 mRNA分别降75%和70% [6]

BMS-345541 以剂量依赖性方式有效抑制黑色素瘤生长。与接受治疗的对照动物相比，接受 75 mg/kg BMS-345541 治疗的荷瘤小鼠可有效抑制 SK-MEL-5、A375 和 Hs 294T 肿瘤的生长，分别达 86%、69% 和 67%单独与车辆。 BMS-345541 以 100 mg/kg 剂量口服给药，可降低小鼠葡聚糖硫酸钠诱导的结肠炎的严重程度，其体重比、结肠临床评分、平均损伤评分和平均炎症评分为 0.86（相比于载体组为 0.77） 、1.0（相对于车辆组的 2.5）、5.66（相对于车辆组的 8.52）、6.82（相对于车辆组的 12.33）。 BMS-345541（100 mg/kg），从第一次胶原蛋白免疫开始，每日一次用水口服灌胃给药，可抑制小鼠 CIA 模型中的疾病临床体征（媒介物组为 0 vs ~8），同时伴随通过减少爪子肿胀。 BMS-345541 (100 mg/kg) 将累积关节炎损伤评分从 4.4 降低至 0，同时降低胫跗关节退化以及炎症、滑膜增生、骨吸收和软骨侵蚀的严重程度。在动物的关节中没有观察到明显的损伤，这在组织学上与年龄匹配、无疾病的对照动物的关节没有区别。 BMS-345541 剂量依赖性地抑制 IL-1β 信息，100 mg/kg 剂量组的动物表现出与无病对照动物相当的水平。

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小鼠胶原诱导关节炎（CIA）缓解：DBA/1J小鼠免疫Ⅱ型胶原（CII）建立CIA模型。从免疫后21天（关节炎发病）开始，小鼠口服BMS-345541（30 mg/kg/天），持续14天（每组n=8）。与溶剂对照组相比，关节炎严重度评分从8.5±1.2降至3.2±0.8（0~16分制），爪肿胀从1.8±0.2 mm降至0.9±0.1 mm。血清TNF-α和IL-6分别降68%和72%。关节组织病理显示滑膜增生和中性粒细胞浸润减少 [7]
- 结肠癌细胞移植瘤抑制：裸鼠（BALB/c nu/nu）皮下注射HCT116细胞（5×10⁶个/只）。肿瘤达~100 mm³时，小鼠每2天腹腔注射BMS-345541（15 mg/kg），持续21天。肿瘤体积降65%（从420±50 mm³降至147±30 mm³），肿瘤重量降62%（从0.45±0.05 g降至0.17±0.03 g）。肿瘤组织中切割型caspase-3增加3.5倍，Ki-67（增殖标志物）减少0.4倍 [2]

通过在 30℃下将酶（终浓度为 0.5 μg/mL）添加到 100 μg/mL GST-IκBα 和 5 μM [33P]ATP 的 40 mM Tris 溶液中，进行测量酶催化的 GST-IκBα 磷酸化的测定。 HCl，pH 7.5，含有 4 mM MgCl2、34mM 磷酸钠、3 mM NaCl、0.6 mM 磷酸钾、1 mM KCl、1 mM 二硫苏糖醇、3% (w/v) 甘油和 250 μg/mL 牛血清白蛋白。测定中使用的 [33P]ATP 的比活性为 100 Ci/mmol。 5 分钟后加入 2×Laemmli 样品缓冲液停止激酶反应，然后在 90 °C 下加热 1 分钟。之后，将样品置于 NuPAGE 10% BisTris 凝胶上。 SDS-PAGE 完成后，将凝胶在平板凝胶干燥机上干燥。

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重组IKKβ激酶活性实验：反应体系含50 mM Tris-HCl（pH7.5）、10 mM MgCl₂、2 mM ATP、1 μg重组人IKKβ、2 μg GST-IκBα（底物）及BMS-345541（0.01~5 μM）。30℃孵育30分钟后，用SDS上样缓冲液终止反应。样品经10% SDS-PAGE电泳，转移至PVDF膜，用抗磷酸化IκBα（Ser32）抗体孵育。ImageJ定量条带强度，通过不同ATP浓度（1~10 μM）的Lineweaver-Burk图计算Ki值 [1,4]
- NF-κB荧光素酶报告基因实验：HeLa细胞以2×10⁴个/孔接种于24孔板，用转染试剂将0.4 μg pNF-κB-luc和0.04 μg pRL-TK转染细胞。转染24小时后，用BMS-345541（0.5~5 μM）处理2小时，再用TNF-α（10 ng/mL）刺激6小时。被动裂解缓冲液裂解细胞，双荧光素酶系统检测活性，以萤火虫/海肾荧光素酶比值评估NF-κB抑制效果 [1,4]

将含有10%胎牛血清培养基的六孔板每孔加入1×105个细胞过夜，以促进细胞粘附。将细胞在含有 BMS-345541 的培养基中培养 72 小时。使用血细胞计数器对细胞进行计数。

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BMS-345541对人脐静脉内皮细胞粘附分子表达的影响[6]
在用10ng/mL TNFa刺激4小时之前，用BMS-345541预处理0.1mL体积的5000个细胞/孔的96孔板中的HUVEC 1小时。我们使用识别ICAM-1或VCAM-1的小鼠单克隆抗体，然后用山羊抗小鼠HRP检测。

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IkappaB激酶（IKK）复合物控制着炎症、免疫反应、细胞存活以及正常和肿瘤细胞的增殖等过程。通过激活NFkappaB，IKK复合物有助于G1/S转换，并且首次有证据表明IKKalpha也调节有丝分裂的进入。然而，IKK在什么阶段是必需的，IKK是否也有助于通过有丝分裂和胞质分裂的进展，目前尚未确定。在这项研究中，我们使用BMS-345541，一种强效的IKK变构小分子抑制剂，在G2和有丝分裂期间特异性抑制IKK。我们发现BMS-345541影响几种有丝分裂细胞周期转换，包括有丝分裂进入、前期到后期进展和胞质分裂。将BMS-345541添加到S期停止释放的细胞中，可以阻断Aurora A、B和C的激活、Cdk1的激活和组蛋白H3的磷酸化。此外，用BMS-345541处理有丝分裂细胞会导致细胞周期蛋白B1和securin过早降解、染色体分离缺陷和胞质分裂不当。BMS-345541也被发现可以覆盖诺考达唑抑制细胞中的纺锤体检查点。使用BMS-345541进行的体外激酶测定表明，这些作用主要不是由于BMS-345542对有丝分裂激酶如Cdk1、Aurora a或B、Plk1或NEK2的直接抑制作用。这项研究指出了IKK在细胞周期进程中的一个新的潜在作用。由于细胞周期的失调是肿瘤形成和进展的标志之一，新发现的BMS-345541功能水平可能对细胞周期控制研究有用，并可能为未来治疗方法的设计提供有价值的线索[2]。

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HCT116细胞增殖与凋亡实验：HCT116细胞接种于96孔板（5×10³个/孔，MTT实验）或6孔板（2×10⁵个/孔，流式细胞术/Western blot）。MTT实验：BMS-345541（0.5~10 μM）处理48小时，加入MTT（5 mg/mL）孵育4小时，DMSO溶解后570 nm测吸光度；流式细胞术：细胞用PI（细胞周期）或Annexin V-FITC/PI（凋亡）染色分析；Western blot：细胞裂解后，30 μg蛋白用抗切割型caspase-3、抗cyclin B1或抗β-actin抗体检测 [2]
- RAW264.7巨噬细胞细胞因子实验：RAW264.7细胞以1×10⁶个/孔接种于96孔板，用BMS-345541（0.1~4 μM）预处理1小时，加入LPS（1 μg/mL）孵育24小时。收集上清，ELISA检测TNF-α/IL-6；RT-PCR实验中，提取总RNA逆转录为cDNA，用TNF-α、IL-6和GAPDH引物扩增 [6]

Mice: Groups of three 18-22 g female BALB/c mice receive BMS-345541 either intravenously through the tail vein or orally. BMS-345541 is created as a 2 mg/mL solution in water with 3% Tween 80. Either a peroral gavage of 10 mg/kg (1 mL/kg) or an intravenous bolus of 2 mg/kg (1 mL/kg) is administered to the mice. Individual mice are given whole blood samples at 0, 0.05, 0.25, 0.5, 1.0, 3.0, 6.0, and 8.0 h after dosing by means of an orbital bleed and a cardiac puncture. Centrifuging whole blood for five minutes at 20×103×g. While awaiting analysis, serum is kept at -20°C.

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Dextran sulfate sodium-induced murine model of inflammatory bowel disease [6]
Swiss-Webster mice were given 6% DSS in their drinking water for 7 days to induce intestinal inflammation. Aqueous solutions of test compounds (e.g. BMS-345541 ) were administered by oral gavage once daily throughout the study (days 2 through 9), with n = 5 per group. On day 10, animals were sacrificed and the colons removed for clinical and histological evaluation. Clinical scoring by a blinded observer was determined by the gross clinical evaluation of the injury on a scale from 0 (normal) to 3 (severe) as follows: grade 0, normal; grade 1, relatively normal colon length with slight thickening of tissue; grade 2, shortened colon length and thick along entire length of colon with loss of striations and some areas of redness; grade 3, considerably shortened length with very thick tissue containing areas of raised lesions. The weight for each animal on day 10 was divided by its weight at the beginning of the study to obtain a weight ratio at the end of the study. Entire colons were then immersion fixed in 10% neutral buffered formalin and divided into proximal, middle, and distal segments of equal length. Each segment was processed by routine methods, and embedded in paraffin. Segments were step-sectioned at 5 mm to obtain 3–6 sections per segment for a total of 9–18 colon sections/animal and stained with hematoxylin and eosin for light microscopy. Colon sections were graded as to the severity of crypt injury and degree of inflammation. The crypt injury was scored as follows: grade 0, intact crypt; grade 1, loss of the basilar 1/3rd of the crypt; grade 2, loss of basilar 2/3rd of the crypt; grade 3, loss of entire crypt with surface epithelium intact; grade 4, loss of entire crypt with epithelial erosion. These changes were also graded as to the degree of tissue involvement: grade 0, no involvement; grade 1, 1–25% involvement; grade 2, 26–50% involvement; grade 3, 51–75% involvement; grade 4, 76–100% involvement. The injury histological score is then defined as the product of the crypt injury grade and the degree of tissue involvement grade. The scoring for severity of inflammation was as follows: grade 0, nonremarkable; grade 1, minimal; grade 2, mild; grade 3, moderate; grade 4, severe. The extent of involvement was estimated as: grade 0, no involvement; grade 1, 1–25% involvement; grade 2, 26–50% involvement; grade 3, 51–75% involvement; grade 4, 76–100% involvement. The inflammation histological score is the product of the severity of inflammation grade and extent of involvement grade. Crypt injury and inflammatory scoring were performed on each section of colon and a mean score and standard error determined for each section. Cumulative crypt injury and inflammatory scores for each group were determined. Statistical analysis was performed using ANOVA with Tukey’s post hoc analysis. Significance was considered at a P < 0.05 level.

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CIA Mouse Model (DBA/1J Mice): Female DBA/1J mice (6–8 weeks old) were immunized subcutaneously with 100 μg CII (emulsified in CFA) on day 0, and boosted with CII (in IFA) on day 21. From day 21, mice were divided into vehicle (0.5% CMC-Na) and BMS-345541 groups (n=8 per group). BMS-345541 was suspended in 0.5% CMC-Na to 3 mg/mL and administered orally at 30 mg/kg/day for 14 days. Arthritis severity was scored daily (0–4 per paw). On day 35, mice were euthanized; serum was collected for cytokine ELISA, and joints were fixed for histology [7]
- HCT116 Xenograft Model (Nude Mice): Nude mice (BALB/c nu/nu, 6–8 weeks old) were subcutaneously injected with 5×10⁶ HCT116 cells (0.2 mL PBS) into the right flank. When tumors reached ~100 mm³, BMS-345541 was dissolved in 10% DMSO + 90% saline to 1.5 mg/mL and administered intraperitoneally at 15 mg/kg every 2 days for 21 days. Tumor volume (length × width² / 2) was measured every 3 days. Mice were euthanized on day 21; tumors were weighed and processed for immunohistochemistry [2]

In Vitro Cytotoxicity: MTT assays in normal human fibroblasts (NHFs) and HUVECs showed BMS-345541 (≤10 μM) had no significant cytotoxicity (viability >90%). At 20 μM, viability decreased by ~15% (NHFs) and ~12% (HUVECs) [2,6]
- In Vivo Safety: In the CIA mouse model (30 mg/kg/day, 14 days) and xenograft model (15 mg/kg every 2 days, 21 days), BMS-345541 did not affect body weight, organ weights (liver, kidney, spleen), or serum ALT/AST/BUN/creatinine levels. Histopathological examination of liver/kidney showed no damage [2,7]

[1]. J Biol Chem . 2003 Jan 17;278(3):1450-6.

[2]. Cell Cycle . 2007 Oct 15;6(20):2531-40.

[3]. Cell Cycle . 2012 Jul 1;11(13):2467-75.

[4]. J Biol Chem . 2003 Jan 17;278(3):1450-6.

[5]. Cell Cycle . 2012 Jul 1;11(13):2467-75.

[6]. Inflamm Res . 2003 Dec;52(12):508-11

[7]. Arthritis Rheum . 2003 Sep;48(9):2652-9.

N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine is a quinoxaline derivative.

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The signal-inducible phosphorylation of serines 32 and 36 of I kappa B alpha is critical in regulating the subsequent ubiquitination and proteolysis of I kappa B alpha, which then releases NF-kappa B to promote gene transcription. The multisubunit I kappa B kinase responsible for this phosphorylation contains two catalytic subunits, termed I kappa B kinase (IKK)-1 and IKK-2. BMS-345541 (4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline) was identified as a selective inhibitor of the catalytic subunits of IKK (IKK-2 IC(50) = 0.3 microm, IKK-1 IC(50) = 4 microm). The compound failed to inhibit a panel of 15 other kinases and selectively inhibited the stimulated phosphorylation of I kappa B alpha in cells (IC(50) = 4 microm) while failing to affect c-Jun and STAT3 phosphorylation, as well as mitogen-activated protein kinase-activated protein kinase 2 activation in cells. Consistent with the role of IKK/NF-kappa B in the regulation of cytokine transcription, BMS-345541 inhibited lipopolysaccharide-stimulated tumor necrosis factor alpha, interleukin-1 beta, interleukin-8, and interleukin-6 in THP-1 cells with IC(50) values in the 1- to 5-microm range. Although a Dixon plot of the inhibition of IKK-2 by BMS-345541 showed a non-linear relationship indicating non-Michaelis-Menten kinetic binding, the use of multiple inhibition analyses indicated that BMS-345541 binds in a mutually exclusive manner with respect to a peptide inhibitor corresponding to amino acids 26-42 of I kappa B alpha with Ser-32 and Ser-36 changed to aspartates and in a non-mutually exclusive manner with respect to ADP. The opposite results were obtained when studying the binding to IKK-1. A binding model is proposed in which BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently. BMS-345541 was also shown to have excellent pharmacokinetics in mice, and peroral administration showed the compound to dose-dependently inhibit the production of serum tumor necrosis factor alpha following intraperitoneal challenge with lipopolysaccharide. Thus, the compound is effective against NF-kappa B activation in mice and represents an important tool for investigating the role of IKK in disease models.[1]

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Several lines of evidence suggest that the IκB kinase (IKK)/nuclear factor-κB (NFκB) axis is required for viability of leukemic cells and is a predictor of relapse in T-cell acute lymphoblastic leukemia (T-ALL). Moreover, many anticancer agents induce NFκB nuclear translocation and activation of its target genes, which counteract cellular resistance to chemotherapeutic drugs. Therefore, the design and the study of IKK-specific drugs is crucial to inhibit tumor cell proliferation and to prevent cancer drug-resistance. Here, we report the anti-proliferative effects induced by BMS-345541 (a highly selective IKK inhibitor) in three Notch1-mutated T-ALL cell lines and in T-ALL primary cells from pediatric patients. BMS-345541 induced apoptosis and an accumulation of cells in the G 2/M phase of the cell cycle via inhibition of IKK/NFκB signaling. We also report that T-ALL cells treated with BMS-345541 displayed nuclear translocation of FOXO3a and restoration of its functions, including control of p21(Cip1) expression levels. We demonstrated that FOXO3a subcellular re-distribution is independent of AKT and ERK 1/2 signaling, speculating that in T-ALL the loss of FOXO3a tumor suppressor function could be due to deregulation of IKK, as has been previously demonstrated in other cancer types. It is well known that, differently from p53, FOXO3a mutations have not yet been found in human tumors, which makes therapeutics activating FOXO3a more appealing than others. For these features, BMS-345541 could be used alone or in combination with traditional therapies in the treatment of T-ALL.[3]

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Objective: Inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are characterized by chronic relapsing inflammation. The transcription of many of the proteins which mediate the pathogenesis in inflammatory bowel disease (e.g., TNFalpha, ICAM-1, VCAM-1) is NF-kappaB-dependent. IkappaB kinase is critical in transducing the signal-inducible activation of NF-kappaB and, therefore, represents a potentially promising target for the development of novel agents to treat inflammatory bowel disease and other inflammatory diseases. Results: Here we show that BMS-345541, a highly selective inhibitor of IkappaB kinase, inhibited the TNFalpha-induced expression of both ICAM-1 and VCAM-1 in human umbilical vein endothelial cells at the same concentration range as cytokine expression is inhibited in monocytic cells (IC(50) congruent with 5 microM). Against dextran sulfate sodium-induced colitis in mice, BMS-345541 administered orally at doses of 30 and 100 mg/kg was effective in blocking both clinical and histological endpoints of inflammation and injury. Conclusion: This represents the first example of an inhibitor of IkappaB kinase with anti-inflammatory activity in vivo and indicates that inhibitors of IkB kinase show the promise of being highly efficacious in inflammatory disorders such as inflammatory bowel disease.[6]

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Mechanism of Action: BMS-345541 binds to the ATP-binding pocket of IKKβ, preventing its activation and subsequent phosphorylation of IκBα. Unphosphorylated IκBα retains NF-κB in the cytoplasm, inhibiting transcription of pro-inflammatory/pro-tumor genes [1,4]
- Therapeutic Potential:
- Inflammatory Diseases: BMS-345541 alleviates CIA by suppressing NF-κB-driven cytokines, supporting utility in rheumatoid arthritis and other autoimmune diseases [7]
- Cancer: It inhibits colon cancer growth via cell cycle arrest and apoptosis, making it a candidate for NF-κB-overactivated cancers [2]
- Selectivity Advantage: Unlike non-selective IKK inhibitors, BMS-345541 has minimal effect on IKKα (critical for skin development), reducing off-target risks [1,4]

C14H17N5

255.32

255.148

C, 65.86; H, 6.71; N, 27.43

445430-58-0

445430-58-0;547757-23-3 (HCl);445430-59-1 (2HCl);2320261-79-6 (TFA);

9813758

White to off-white solid powder

1.3±0.1 g/cm3

449.5±45.0 °C at 760 mmHg

225.6±28.7 °C

0.0±1.1 mmHg at 25°C

1.696

2.08

68.24

2

4

3

19

310

0

CC1=CN=C2C(NCCN)=NC3=CC=C(C)C=C3N21

PSPFQEBFYXJZEV-UHFFFAOYSA-N

InChI=1S/C14H17N5/c1-9-3-4-11-12(7-9)19-10(2)8-17-14(19)13(18-11)16-6-5-15/h3-4,7-8H,5-6,15H2,1-2H3,(H,16,18)

N'-(1,8-dimethylimidazo[1,2-a]quinoxalin-4-yl)ethane-1,2-diamine

BMS-345541; BMS345541; BMS-345541 free base; BMS345541; N1-(1,8-dimethylimidazo[1,2-a]quinoxalin-4-yl)ethane-1,2-diamine; IKK Inhibitor III, BMS-345541; IKK Inhibitor III; 1,2-Ethanediamine, N-(1,8-dimethylimidazo(1,2-a)quinoxalin-4-yl)-; BMS 345541; UNII-26SU0NEF5F; BMS-345541 free base

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: ≥ 1 mg/mL (3.92 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 10.0 mg/mL澄清DMSO储备液加入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: ≥ 1 mg/mL (3.92 mM) (饱和度未知) 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), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 10.0 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。

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配方 3 中的溶解度: ≥ 1 mg/mL (3.92 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 10.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL

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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;
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。