IKK-16 (hydrochloride)

IKK-16 (hydrochloride) is a novel, orally active selective inhibitor of IκB kinase (IKK), with IC₅₀ values of 40nM, 70nM, and 200nM against IKK-2, IKK complex, and IKK-1^[1-2]. IKK-16 shows potential applications in research areas such as sepsis, acute inflammation models, and prostate cancer^[3-4].

In vitro, treatment of SKBR3 cells with 5µM IKK-16 for 24 hours significantly inhibited cell viability, reduced interactions between PTPIP51 and RelA/IκB, enhanced the association of PTPIP51 with the Her2 receptor, and weakened the interaction between PTPIP51 and PTP1B^[5]. In HepG2 cells, combined treatment with 5µM IKK-16 and deoxyelephantopin (DET; 10–100µM) for 24 hours, IKK-16 further enhanced DET-induced cytotoxicity and synergistically suppressed nuclear translocation of NF-κB p65^[6].

In vivo, in LPS/PepG-induced multiple organ dysfunction models and cecal ligation and puncture (CLP)-induced sepsis models, intravenous administration of IKK-16 (1mg/kg) 1 hour after induction, IKK-16 significantly alleviated sepsis-related cardiac dysfunction, renal impairment, hepatocellular injury, and pulmonary inflammation. IKK-16 also reduced phosphorylation of IκBα, nuclear translocation of NF-κB p65 subunit, and expression of inducible nitric oxide synthase (iNOS) in cardiac and hepatic tissues^[7]. In a 5/6 nephrectomy-induced chronic kidney disease (CKD) mouse model, intravenous administration of IKK-16 (1mg/kg) 1 hour after LPS challenge (2mg/kg) or CLP surgery, IKK-16 markedly attenuated sepsis-aggravated cardiac dysfunction and pulmonary inflammation, lowered plasma levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), and suppressed phosphorylation of IKKα/β and IκBα, nuclear translocation of p65 NF-κB, and iNOS expression in cardiac tissues^[8].

References:
[1] Waelchli R, Bollbuck B, Bruns C, et al. Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. Bioorg Med Chem Lett. 2006 Jan 1;16(1):108-12.
[2] Mu Y, Cory TJ. Suppression of HIV-1 Viral Replication by Inhibiting Drug Efflux Transporters in Activated Macrophages. Curr HIV Res. 2021;19(2):128-137.
[3] Galbraith NJ, Manek S, Walker S, et al. The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes. Immunobiology. 2018 Apr-May;223(4-5):365-373.
[4] Zhang K, Yang J, Yang QQ, et al. ER stress genes (COL1A1, LOXL2, VWF) predicts IKK-16 as a Candidate therapeutic target for colitis-related inflammation and fibrosis suppression. Front Immunol. 2025 Jun 18;16:1587860.
[5] Dietel E, Brobeil A, Tag C, et al. PTPIP51 crosslinks the NFκB signaling and the MAPK pathway in SKBR3 cells. Future Sci OA. 2020 Mar 4;6(5):FSO463.
[6] Mehmood T, Maryam A, Zhang H, et al. Deoxyelephantopin induces apoptosis in HepG2 cells via oxidative stress, NF-κB inhibition and mitochondrial dysfunction. Biofactors. 2017 Jan 2;43(1):63-72.
[7] Coldewey SM, Rogazzo M, Collino M, et al. Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse. Dis Model Mech. 2013 Jul;6(4):1031-42.
[8] Chen J, Kieswich JE, Chiazza F, et al. IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD. J Am Soc Nephrol. 2017 Jan;28(1):94-105.

IKK-16 (hydrochloride)是一种新型的、具有口服活性的选择性IκB激酶（IKK）抑制剂，IKK-16作用于IKK-2、IKK复合物和IKK-1的IC₅₀值分别为40nM、70nM和200nM^[1-2]。IKK-16在败血症、急性炎症模型及前列腺癌等相关研究中显示出潜在的应用价值^[3-4]。

在体外，IKK-16（5μM）处理SKBR3细胞24小时，IKK-16显著抑制细胞活力，并减少PTPIP51与RelA、IκB的相互作用，IKK-16增强PTPIP51与Her2受体的结合，IKK-16还削弱PTPIP51与PTP1B的相互作用^[5]。IKK-16（5μM）与脱氧苦菊素（DET；10-100μM）联合处理HepG2细胞24小时，IKK-16进一步增强DET诱导的细胞毒性，并协同抑制NF-κB p65的核转位^[6]。

在体内，在LPS/PepG诱导的多器官功能障碍模型和盲肠结扎穿刺（CLP）诱导的脓毒症模型小1小时后，IKK-16（1mg/kg）静脉注射处理，IKK-16显著减轻了脓毒症相关的心脏功能障碍、肾功能障碍、肝细胞损伤和肺部炎症，并减弱了心脏和肝脏组织中IκBα磷酸化、NF-κB p65亚基核转位以及诱导型一氧化氮合酶（iNOS）的表达^[7]。在5/6肾切除诱导的慢性肾脏病（CKD）小鼠模型中，接受LPS（2mg/kg）攻击或CLP诱导脓毒症时，IKK-16（1mg/kg）静脉注射处理（在CLP手术后或LPS给药后1小时给药），IKK-16显著减轻了脓毒症加重的心脏功能障碍和肺部炎症，降低了血浆促炎细胞因子（TNF-α, IL-1β, IL-6, IL-10）水平，并减弱了心脏组织中IKKα/β和IκBα磷酸化、p65 NF-κB核转位以及iNOS的表达^[8]。