Bay 11-7821 is an inhibitor of IκBα phosphorylation and NF-κB, selectively and irreversibly inhibits TNF-α-induced IκB-α phosphorylation (IC50 value is approximately 10μM), and reduces the expression of NF-κB and adhesion molecules [1]. Bay 11-7821 inhibits ubiquitin-specific proteases USP7 and USP21 with IC50 values of 0.19 and 0.96μM, respectively [2]. Bay 11-7821 inhibits the formation of pores in liposomes by the pore-forming protein gasdermin D (GSDMD), as well as inflammasome-mediated apoptosis and IL-1β secretion [3].
In vitro, Bay 11-7821 (0-30μM) treated gastric cancer cells (HGC-27, NCI-N87, AGS and MGC80-3) for 24h, inhibited cell viability in a dose-dependent manner, Bcl-2 (total and phosphorylated forms) were significantly downregulated, while Bax was upregulated, and induced S phase arrest by inhibiting cyclin A and CDK-2 expression [4]. Bay 11-7821 (3μM) treated HBL-1 cells for 24-72h, inhibited IκB-α phosphorylation and NF-κB activation, and induced cell death [5]. Bay 11-7821 (30μM) treated KMS-12-BM and MM.1S MM cells rapidly induced cell death, with decreased viability detected within 1h, and complete inhibition of cell viability was achieved within 2-4 hours [6].
In vivo, intraperitoneal injection of Bay 11-7821 (1, 3 mg/kg) in diabetic rats with renal dysfunction significantly improved the decreased levels of SOD and GSH, as well as the increased levels of lipid peroxidation and nitric oxide, and restored the renal histological structure of diabetic rats [7].
References:
[1] Pierce J W, Schoenleber R, Jesmok G, et al. Novel inhibitors of cytokine-induced IκBα phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo[J]. Journal of Biological Chemistry, 1997, 272(34): 21096-21103.
[2] Ritorto M S, Ewan R, Perez-Oliva A B, et al. Screening of DUB activity and specificity by MALDI-TOF mass spectrometry[J]. Nature communications, 2014, 5(1): 4763.
[3] Hu J J, Liu X, Zhao J, et al. Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D[J]. BioRxiv, 2018: 365908.
[4] Chen L, Ruan Y, Wang X, et al. BAY 11-7082, a nuclear factor-κB inhibitor, induces apoptosis and S phase arrest in gastric cancer cells[J]. Journal of gastroenterology, 2014, 49: 864-874.
[5] Strickson S, Campbell D G, Emmerich C H, et al. The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system[J]. Biochemical Journal, 2013, 451(3): 427-437.
[6] Rauert-Wunderlich H, Siegmund D, Maier E, et al. The IKK inhibitor Bay 11-7082 induces cell death independent from inhibition of activation of NFκB transcription factors[J]. PloS one, 2013, 8(3): e59292.
[7] Kolati S R, Kasala E R, Bodduluru L N, et al. BAY 11-7082 ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress and renal inflammation via NF-κB pathway[J]. Environmental Toxicology and Pharmacology, 2015, 39(2): 690-699.
Bay 11-7821是一种IκBα磷酸化和NF-κB抑制剂，选择性且不可逆地抑制TNF-α诱导的IκB-α磷酸化（IC50值约为10μM），并减少NF-κB和粘附分子的表达[1]。Bay 11-7821抑制泛素特异性蛋白酶USP7和USP21，IC50分别为0.19、0.96μM[2]。Bay 11-7821抑制脂质体中的成孔蛋白gasdermin D （GSDMD）孔的形成，以及炎性体介导的细胞凋亡和IL-1β的分泌[3]。
在体外，Bay 11-7821（0-30μM）处理胃癌细胞（HGC-27、NCI-N87、AGS和MGC80-3）24h，以剂量依赖性方式抑制了细胞活力，Bcl-2（总形式和磷酸化形式）均显著下调，而Bax则相反上调，还通过抑制细胞周期蛋白A和 CDK-2表达来诱导S期停滞[4]。Bay 11-7821（3μM）处理HBL-1细胞24-72h，抑制了IκB-α的磷酸化和NF-κB的激活，诱导了细胞死亡[5]。Bay 11-7821（30μM）处理KMS-12-BM和MM.1S MM细胞，快速诱导了细胞死亡，1h就检测到活力降低，且在2-4小时内达到完全抑制细胞活力的效果[6]。
在体内，Bay 11-7821（1、3mg/kg）通过腹腔注射治疗肾功能障碍的糖尿病大鼠，显著改善了SOD、GSH水平降低以及脂质过氧化、一氧化氮水平升高，恢复了糖尿病大鼠的肾脏组织学结构[7]。