AbMole丨NF-κB通路的高引用抑制剂及其在肿瘤和炎症研究中的应用

NF-κB信号通路是调节细胞免疫应答与炎症反应、细胞存活与增殖的核心通路之一。NF-κB家族由多个成员组成，包括p50、p52、p65(RelA）、RelB和c-Rel等。这些成员通过形成同源或异源二聚体发挥功能：结合到靶基因启动子区域的κB位点，调控基因表达，其中p50/p65异源二聚体是最常见且研究最广泛的组合形式。NF-κB通路的发现距今已有近40年历史，在此期间围绕该通路开发了一系列小分子抑制剂，它们为探究NF-κB通路的生物学功能、研究该靶点相关疾病的机理作出了重大贡献。

图 1经典与非经典的NF-κB通路[1]

1.BAY 11-7082 （BAY 11-7821）

BAY 11-7082（NF-κB inhibitor 13，AbMole，M2040）是一种经典的NF-κB通路抑制剂，主要通过阻断IκB激酶（IKKβ）的活性，从而阻止IκBα的磷酸化和降解，最终抑制NF-κB p65亚基的核转位。BAY 11-7082还是一种泛素化系统的抑制剂，可通过抑制E2连接酶（如Ubc13和UbcH7）和E3泛素连接酶（如LUBAC）来阻止线性多泛素链的形成[2]。此外，BAY 11-7082还能直接抑制NLRP3炎症小体的组装及其下游效应分子（如caspase-1、IL-1β和IL-18）的释放[3]。BAY 11-7082具有显著的抗炎活性，大鼠实验显示，BAY 11-7082可缓解实验性自身免疫性神经炎（EAN）的症状，其机制涉及降低M1型巨噬细胞的比例和促炎细胞因子表达[4]。在银屑病样皮炎小鼠模型中，BAY 11-7082（CAS No.：19542-67-7）通过同时抑制NF-κB和NLRP3炎症小体，显著改善皮肤炎症[5]。此外，BAY 11-7082（BAY 11-7821）在高脂饮食诱导的代谢紊乱小鼠中，能降低肝脏和肾脏中NLRP3、caspase-1及IL-1β的水平[6]。BAY 11-7082还可诱导肿瘤细胞的凋亡，例如诱导多药耐药白血病T细胞系的凋亡[7]。

图 2. AbMole的BAY 11-7082（BAY 11-7821，AbMole，M2040）被用于抑制NF-κB p65亚基入核[8]

2.JSH-23

JSH-23（AbMole，M2786）是一种核因子κB（NF-κB）通路的抑制剂，IC50为 7.1 μM，与BAY 11-7082类似，也通过靶向NF-κB p65亚基的核转位发挥调控作用。JSH-23可通过抑制NF-κB信号通路的激活，从而下调促炎因子（如IL-6、TNF-α）的表达。JSH-23在LPS（Lipopolysaccharides，脂多糖）诱导的脓毒症模型小鼠中，JSH-23（3 mg/kg）通过抑制NF-κB通路减轻了心脏损伤，并减少了M1型巨噬细胞极化[9]。JSH-23（CAS No.：749886-87-1）在SD大鼠骨质疏松模型中通过TRAF6/Rac1/NOX1通路抑制破骨细胞分化，同时增强成骨细胞的Nrf2/HO-1表达以维持骨稳态[10]。JSH-23也具有抗肿瘤活性，它可抑制MDA-MB-468三阴性乳腺癌细胞的增殖与迁移，并在HepG2肝癌细胞中通过诱导G2/M期阻滞抑制细胞生长。JSH-23在阿尔茨海默病相关研究中，可恢复Aβ肽注射后的大鼠海马CA1锥体神经元的电生理特性，逆转异常增强的Ih电流[11]。这些研究共同表明，JSH-23作为NF-κB通路的工具分子，在炎症调控、肿瘤干预、神经保护及骨代谢研究中具有重要价值。

图 3. AbMole的JSH-23（AbMole，M2786）抑制RAW264.7细胞中的NF-κB通路的激活和细胞因子mIFN-β的释放[12]。

3.QNZ（EVP4593）

QNZ（EVP4593，AbMole，M2298）是一种NF-κB抑制剂，可抑制 NF-κB 的转录调节活性（IC50为11 nM），QNZ通过靶向抑制p65蛋白（RelA亚基）发挥调控作用。EVP4593可在大鼠肺组织中抑制TLR4/MyD88/NF-κB信号通路，进而调控肺部的炎症反应。此外，EVP4593还是一种能够抑制Orai（钙释放激活钙通道）和TRPC（经典瞬时受体电位离子通道）的化合物，同时对SOCs（内源性储存操作钙通道）也表现出抑制作用[13]。QNZ（CAS No.：545380-34-5）不仅通过调节上述离子通道在亨廷顿病（HD）研究中有效降低突变型亨廷顿蛋白水平，还在诱导多能干细胞（iPSCs）分化的神经元模型中表现出神经保护作用[14]。

图 4. AbMole的QNZ（1 mg/kg/d）（EVP4593，AbMole，M2298）被用于小鼠注射以调控NF-κB信号通路[15]

4.Andrographolide（穿心莲内酯）

Andrographolide（ANDRO，穿心莲内酯，AbMole，M6444）是一种从植物穿心莲（Andrographis paniculata）中分离的二萜内酯化合物，具有抗炎、抗肿瘤、抗氧化等多种生物活性。Andrographolide（Andrographis）还是一种NF-κB信号通路的抑制剂，可通过共价修饰p50 的半胱氨酸残基，抑制NF-κB的激活。Andrographolide（CAS No.：5508-58-7）在Toll样受体（TLR）信号通路中，抑制TLR3和TLR4诱导的NF-κB活化，能显著降低COX-2等促炎因子的表达[16]。另外，Andrographolide还能直接干扰NF-κB与DNA启动子区域的结合，从而阻断下游促炎基因的转录[17]。

5.Dehydroxymethylepoxyquinomicin（DHMEQ）

Dehydroxymethylepoxyquinomicin (DHMEQ，AbMole，M11454）是一种基于微生物次级代谢产物Eepoxyquinomicin C的结构设计合成的特异性NF-κB抑制剂[18]。DHMEQ（CAS No.：287194-40-5）主要通过环氧基团与NF-κB组分中特定半胱氨酸残基的SH基团结合，从而阻断NF-κB的DNA结合能力，抑制其转录活性[18]。DHMEQ作为特异性的NF-κB抑制剂，在探究NF-κB与炎症/肿瘤的相关信号网络方面具有重要价值[19]。例如DHMEQ可增加前列腺癌细胞对放疗的敏感性[20]，以及在胰岛组织的小鼠移植模型中降低组织损伤[21]。

6.IMD-0354

IMD-0354（AbMole，M2769）是一种小分子IKKβ抑制剂，通过选择性阻断IKKβ活性，有效抑制经典NF-κB信号通路的激活[22]。IMD-0354（IKK2 Inhibitor V）的应用广泛，覆盖炎症、肿瘤及代谢研究。在细胞模型中，IMD-0354能有效抑制多种肿瘤细胞（如肺癌细胞、黑色素瘤细胞）的增殖，并通过阻断NF-κB依赖的MET激活，增强细胞对凋亡的敏感性[23]。IMD-0354还在小鼠过敏性炎症模型表现出抗过敏和抗炎效果，其核心机制同样依赖于对NF-κB通路的抑制[24]。

图 5.AbMole的IMD-0354（AbMole，M2769）在AT2细胞中成功抑制了NF-κB信号通路。

7.Caffeic Acid Phenethyl Ester（咖啡酸苯乙酯）

Caffeic Acid Phenethyl Ester（CAPE，咖啡酸苯乙酯，AbMole，M2484）是一种从蜂胶中提取的生物活性多酚酯，具有广泛的科研应用价值。其作用机理主要涉及抗氧化、抗炎、抑制NF-κB信号通路等。CAPE可在微摩尔浓度下抑制NF-κB通路，降低炎症因子的表达，因此具有强大的抗炎活性。例如Caffeic Acid Phenethyl Ester（CAS No.：104594-70-9）在胶原抗体诱导的关节炎小鼠中以 1 mg/kg的剂量，能显著减轻关节炎症和骨破坏[25]。类似地，CAPE 在牙周炎大鼠模型中以10 μmol/kg/天的剂量腹腔注射 14 天，能降低血清炎症因子（IL-1β、TNF-α）的水平[26]。Caffeic Acid Phenethyl Ester还具有抗菌和抗肿瘤活性，例如有文献使用CAPE 并在1 nM至10 μM 浓度范围内测试其细胞活性，其中 10 μM的浓度显著抑制了骨肉瘤细胞增殖[27]。CAPE7（咖啡酸苯乙酯）对植物乳杆菌的最小抑菌浓度（MIC）为 125 μg/mL[28]。

8.Bay 11-7085（Bay 11-7083）

Bay 11-7085（AbMole，M2435）是一种特异性核因子κB（NF-κB）抑制剂，通过靶向NF-κB信号通路发挥作用。Bay 11-7083（CAS No.：196309-76-9）可抑制IκBα磷酸化，阻断p65核转位，从而下调NF-κB的转录活性[29]。研究表明，Bay 11-7085不仅能直接抑制NF-κB，还能通过诱导PTEN表达间接降低AKT磷酸化[29]。在多种细胞模型中，如人骨肉瘤细胞（143B、MG63）、胃癌细胞（HGC27、MKN45）和神经胶质瘤细胞（U251），Bay 11-7085（BAY 11-7083）以剂量依赖性方式显著抑制细胞增殖、迁移和侵袭能力，同时促进凋亡[30, 31]。例如，在HGC27细胞中，其24小时半数抑制浓度（IC50）为24.88 nM[30]。此外，该化合物还能下调炎症相关蛋白（如NLRP3、IL-1β、IL-18）和上调凋亡标志物（如caspase 3、Bax）的表达[31]。

9.SN50

SN50（AbMole，M10545）是一种特异性抑制核因子κB（NF-κB）信号通路的肽类抑制剂，其核心作用机制是通过阻断NF-κB p65亚基的核转位，从而抑制下游炎症相关基因的激活[32]。也有研究表明，SN50能显著减少NF-κB p65在细胞核内的积累，同时降低胞质和核提取物中p65蛋白水平[33]。SN50（CAS No.：213546-53-3）同样具有抗炎能力，例如可有效抑制LPS（Lipopolysaccharides，脂多糖）诱导的小鼠肺损伤[34]。在大鼠模型中，SN50通过抑制NF-κB核转位，能减轻机械牵拉诱导的炎症反应，并降低内乳动脉中IL-6的生成[35]。

10.SC75741

SC75741（AbMole，M4940）是一种特异性核因子κB（NF-κB）信号通路抑制剂，在多种细胞和动物模型中展现出广泛的科研应用价值。其作用机制主要通过直接抑制NF-κB的激活，从而调控下游炎症、免疫及细胞稳态相关通路。SC75741可以通过激活先天免疫，应对病毒复制和传播[36]，例如保护小鼠（注射剂量为5 mg/kg/天）免受禽流感病毒的感染[37]。SC75741也具有抗肿瘤活性，可协同RIP2抑制剂GSK583抑制肿瘤干细胞[38]。

图 6. AbMole的SC75741（AbMole，M4940）抑制巨噬细胞中的NF-κB通路并降低了炎症因子的表达[39]。

11.PDTC (Pyrrolidinedithiocarbamate ammonium，APDC)

PDTC（吡咯烷二硫代氨基甲酸铵，AbMole，M4005）是一种特异性核因子κB（NF-κB）信号通路抑制剂，通过阻断IκB-α磷酸化和NF-κB p65核转位发挥功能。其生物学活性主要是抑制炎症因子（如TNF-α、IL-6、IL-1β）的表达。在细胞实验中，PDTC表现出多方面的调控作用。在GES-1胃黏膜细胞中，PDTC（2.5-60 μmol/L）可剂量依赖性地抑制壬基酚诱导的NF-κB/NLRP3通路激活，降低炎症因子释放[40]。Pyrrolidinedithiocarbamate ammonium（CAS No.：5108-96-3）在甲状腺癌细胞（BCPAP和PTC3-5）中，能抑制NF-κB蛋白表达，影响细胞增殖和迁移[41]。在动物模型中，PDTC（Ammonium pyrrolidinedithiocarbamate）对多种疾病模型具有改善作用：例如在DSS（Dextran sulfate sodium salt，葡聚糖硫酸钠，AbMole，M9443）诱导的溃疡性结肠炎小鼠中，PDTC通过抑制NF-κB活化，减少Th17细胞比例，降低促炎介质产生[42]。在慢性萎缩性胃炎（CAG）小鼠模型中，PDTC（100-200 mg/kg/day，灌胃8周）可减轻胃黏膜损伤[43]。

图 7. AbMole的Pyrrolidinedithiocarbamate ammonium（PDTC，AbMole，M4005） 被用于探究 NF-κB 信号通路在TLR5 激活中的作用[44]。

参考文献及鸣谢

[1] Guo, Q.; Jin, Y.; Chen, X.; et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal transduction and targeted therapy 2024, 9(1), 53.

[2] Hodge, C. D.; Edwards, R. A.; Markin, C. J.; et al. Covalent inhibition of Ubc13 affects ubiquitin signaling and reveals active site elements important for targeting. 2015, 10(7), 1718-1728.

[3] Irrera, N.; Vaccaro, M.; Bitto, A.; et al. BAY 11-7082 inhibits the NF-κB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis. 2017, 131(6), 487-498.

[4] Shen, D.; Chu, F.; Lang, Y.; et al. Nuclear factor kappa B inhibitor suppresses experimental autoimmune neuritis in mice via declining macrophages polarization to M1 type. Clinical and experimental immunology 2021, 206(1), 110-117.

[5] Irrera, N.; Vaccaro, M.; Bitto, A.; et al. BAY 11-7082 inhibits the NF-kappaB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis. Clinical science (London, England : 1979) 2017, 131(6), 487-498.

[6] Chiazza, F.; Couturier-Maillard, A.; Benetti, E.; et al. Targeting the NLRP3 Inflammasome to Reduce Diet-Induced Metabolic Abnormalities in Mice. Molecular medicine (Cambridge, Mass.) 2016, 21(1), 1025-1037.

[7] García, M. G.; Alaniz, L.; Lopes, E. C.; et al. Inhibition of NF-κB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines. 2005, 29(12), 1425-1434.

[8] Shi, Y.-J.; Li, H.-Q.; Zhao, X.-H. Impact of a Papain-Catalyzed Plastein Reaction of Salmon Skin Gelatin Hydrolysate and Exogenous Amino Acids on Anti-Inflammatory Activity in LPS-Stimulated Macrophages. ACS Food Science & Technology 2025, 5(4), 1591-1600.

[9] Lv, B.; Cao, K.; Chen, Z.; et al. Jieyu I formula and its primary component quercetin alleviate anxiety by modulating neuroregeneration and inflammation via the calcium signaling pathway. Journal of ethnopharmacology 2026, 356, 120820.

[10] Soleimani, Z.; Davoudi, S.; Saffarzadeh, F.; et al. Restoring neuronal excitability and spatial memory through inhibiting amyloid-beta-induced hyperactive NF-kappaB in a rat model of Alzheimer's disease. Brain research 2025, 1861, 149703.

[11] Wang, S.; Lu, M.; Wang, W.; et al. Macrophage Polarization Modulated by NF-kappaB in Polylactide Membranes-Treated Peritendinous Adhesion. Small (Weinheim an der Bergstrasse, Germany) 2022, 18(13), e2104112.

[12] Chen, F.; Li, T.; Zhang, H.; et al. Acid-Ionizable Iron Nanoadjuvant Augments STING Activation for Personalized Vaccination Immunotherapy of Cancer. Advanced materials (Deerfield Beach, Fla.) 2023, 35(10), e2209910.

[13] Chauvet, S.; Jarvis, L.; Chevallet, M.; et al. Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons from Embryonic Mouse Brain. Frontiers in pharmacology 2016, 7, 486.

[14] Grekhnev, D. A.; Kruchinina, A. A.; Vigont, V. A.; et al. The Mystery of EVP4593: Perspectives of the Quinazoline-Derived Compound in the Treatment of Huntington's Disease and Other Human Pathologies. International journal of molecular sciences 2022, 23(24).

[15] Zhang, C.; Lin, Y.; Li, H.; et al. Fatty acid binding protein 4 (FABP4) induces chondrocyte degeneration via activation of the NF-κb signaling pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2024, 38(1), e23347.

[16] Kim, A. Y.; Shim, H. J.; Shin, H. M.; et al. Andrographolide suppresses TRIF-dependent signaling of toll-like receptors by targeting TBK1. International immunopharmacology 2018, 57, 172-180.

[17] Mishra, K. P. Andrographolide: Regulating the Master Regulator NF-kappaB. Indian journal of clinical biochemistry : IJCB 2021, 36(1), 117-119.

[18] Sidthipong, K.; Ma, J.; Yu, W. L.; et al. Rational design, synthesis and in vitro evaluation of novel exo-methylene butyrolactone salicyloylamide as NF-kappaB inhibitor. Bioorganic & medicinal chemistry letters 2017, 27(3), 562-566.

[19] Sehnert, B.; Burkhardt, H.; Dubel, S.; et al. Cell-Type Targeted NF-kappaB Inhibition for the Treatment of Inflammatory Diseases. Cells 2020, 9(7).

[20] Kozakai, N.; Kikuchi, E.; Hasegawa, M.; et al. Enhancement of radiosensitivity by a unique novel NF-κB inhibitor, DHMEQ, in prostate cancer. 2012, 107(4), 652-657.

[21] Watanabe, M.; Yamashita, K.; Kamachi, H.; et al. Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent alloimmune responses and permits long-term islet allograft acceptance. 2013, 96(5), 454-462.

[22] Liu, C.; Chen, W.; Chen, Z.; et al. Studies on the treatment of melanoma with folate acid conjugated dextran and lauryl alcohol loaded with IMD0354. OncoTargets and therapy 2019, 12, 4655-4663.

[23] Wang, R.; Peng, S.; Zhang, X.; et al. Inhibition of NF-kappaB improves sensitivity to irradiation and EGFR-TKIs and decreases irradiation-induced lung toxicity. International journal of cancer 2019, 144(1), 200-209.

[24] Sugita, A.; Ogawa, H.; Azuma, M.; et al. Antiallergic and anti-inflammatory effects of a novel IκB kinase β inhibitor, IMD-0354, in a mouse model of allergic inflammation. 2009, 148(3), 186-198.

[25] Williams, B.; Tsangari, E.; Stansborough, R.; et al. Mixed effects of caffeic acid phenethyl ester (CAPE) on joint inflammation, bone loss and gastrointestinal inflammation in a murine model of collagen antibody-induced arthritis. Inflammopharmacology 2017, 25(1), 55-68.

[26] Yigit, U.; Kirzioglu, F. Y.; Ozmen, O.; et al. Protective effects of caffeic acid phenethyl ester on the heart in experimental periodontitis against oxidative stress in rats. Dental and medical problems 2021, 58(3), 335-341.

[27] Santos, P. H. N.; Silva, H. L.; Martinez, E. F.; et al. Low concentrations of caffeic acid phenethyl ester stimulate osteogenesis in vitro. Tissue & cell 2021, 73, 101618.

[28] Collins, W.; Lowen, N.; Blake, D. J. Caffeic Acid Esters Are Effective Bactericidal Compounds Against Paenibacilluslarvae by Altering Intracellular Oxidant and Antioxidant Levels. Biomolecules 2019, 9(8).

[29] Tan, B.; Yuan, Z.; Zhang, Q.; et al. The NF-kappaB pathway is critically implicated in the oncogenic phenotype of human osteosarcoma cells. Journal of applied biomedicine 2021, 19(4), 190-201.

[30] Yan, Y.; Qian, H.; Cao, Y.; et al. Nuclear factor-kappaB inhibitor Bay11-7082 inhibits gastric cancer cell proliferation by inhibiting Gli1 expression. Oncology letters 2021, 21(4), 301.

[31] Xie, K.; Zhou, D.; Fang, C.; et al. Inhibition of NF-kappaB activation by BAY 11-7821 suppresses the proliferation and inflammation of glioma cells through inducing autophagy. Translational cancer research 2022, 11(2), 403-413.

[32] Zhang, L.; Wang, X.; Zhang, L.; et al. Combination of curcumin and luteolin synergistically inhibits TNF-alpha-induced vascular inflammation in human vascular cells and mice. The Journal of nutritional biochemistry 2019, 73, 108222.

[33] Wang, H. X.; Wang, H. M.; Lin, H. Y.; et al. Proteasome subunit LMP2 is required for matrix metalloproteinase-2 and -9 expression and activities in human invasive extravillous trophoblast cell line. Journal of cellular physiology 2006, 206(3), 616-623.

[34] Chian, C.-F.; Chiang, C.-H.; Chuang, C.-H.; et al. Inhibitor of nuclear factor-κB, SN50, attenuates lipopolysaccharide-induced lung injury in an isolated and perfused rat lung model. 2014, 163(3), 211-220.

[35] Wu, M.; Gu, X.; Li, X.; et al. C-Reactive Protein and Inflammatory Cytokines during Percutaneous Coronary Intervention. Journal of vascular research 2016, 53(1-2), 39-48.

[36] Tian, B.; Cai, D.; Wang, M.; et al. SC75741 antagonizes vesicular stomatitis virus, duck Tembusu virus, and duck plague virus infection in duck cells through promoting innate immune responses. 2021, 100(5), 101085.

[37] Haasbach, E.; Reiling, S. J.; Ehrhardt, C.; et al. The NF-kappaB inhibitor SC75741 protects mice against highly pathogenic avian influenza A virus. 2013, 99(3), 336-344.

[38] Wang, X. L.; Jiao, B. H.; Wu, J. L.; et al. Mechanism of RIP2 enhancing stemness of glioma cells induces temozolomide resistance. CNS neuroscience & therapeutics 2022, 28(12), 2319-2330.

[39] Jiang, Y.; Wang, S.; Zhu, W.; et al. Lysyl Oxidase-Like 1 (LOXL1) Up-Regulation in Chondrocytes Promotes M1 Macrophage Activation in Osteoarthritis via NF-κB and STAT3 Signaling. ImmunoTargets and therapy 2025, 14, 259-278.

[40] Xu, J.; Li, S.; Yang, X.; et al. Mechanism of nonylphenol induced gastric inflammation through NF-kappaB/NLRP3 signaling pathway. Toxicology 2022, 479, 153294.

[41] Zhou, D.; Li, Z.; Bai, X. BRAFV600E and RET/PTC Promote Proliferation and Migration of Papillary Thyroid Carcinoma Cells In Vitro by Regulating Nuclear Factor-kappaB. Medical science monitor : international medical journal of experimental and clinical research 2017, 23, 5321-5329.

[42] Guo, Y. E.; Lv, J.; Shu, P.; et al. Drug screening identifies pyrrolidinedithiocarbamate ammonium ameliorating DSS-induced mouse ulcerative colitis via suppressing Th17 differentiation. Cellular immunology 2024, 405-406, 104887.

[43] Jiang, J. Y.; Liu, D. J.; Liu, M. X. The protective effect of NF-kappaB signaling pathway inhibitor PDTC on mice with chronic atrophic gastritis. Scandinavian journal of gastroenterology 2021, 56(10), 1131-1139.

[44] Tahoun, A.; Jensen, K.; Corripio-Miyar, Y.; et al. Host species adaptation of TLR5 signalling and flagellin recognition. Scientific reports 2017, 7(1), 17677.