il-4-inhibitor-1

IL-4-inhibitor-1 是 IL-4 的抑制剂 (EC50 = 1.81 µM)。

BI-69A11 ((E)-3-(1H-Benzo[d]imidazol-2-yl)-1-(6-chloro-2-hydroxy-4-phenylquinolin-3-yl)prop-2-en-1-one) 是一种双重 AKT 和 NFkB 通路抑制剂。它通过靶向 Akt 增强结肠癌细胞对 mda-7 IL-24 诱导的生长抑制的敏感性。

MRT67307 是一种IKKε和TBK-1的双抑制剂，IC50分别为 160 和 19 nM。它抑制细胞自噬，也可抑制ULK1和ULK2，IC50分别为 45 和 38 nM。

IRAK4-IN-4 （化合物 15） 是白介素-1 受体相关激酶抑制剂，IC50为 2.8 nM。它还抑制环 GMP-AM 合酶 ，IC50为 2.1 nM。

AZ1495 是一种口服有活性的白介素-1受体相关激酶 4(IRAK4)抑制剂，能够作用于 IRAK4 (IC50:5 nM)和 IRAK1 (IC50:23 nM)。可用于研究突变型 MYD88L265P 弥漫性 B 细胞淋巴瘤 (DLBCL) 。

PQA-18 是p21激活激酶2（PAK2；IC50 = 10 nM）的有效抑制剂，并作为Ppc-1（产品编号42352）衍生物展现出免疫抑制特性。该化合物能够降低由刀豆A（产品编号14951）刺激的Jurkat T细胞中IL-2的生成（IC50 = 400 nM）。在应用0.1% PQA-18的情况下，NC Nga小鼠模型显示异位性皮炎的严重程度、血清IgE水平及皮肤厚度有所减轻。此外，0.05%的剂量可有效减少该小鼠模型中皮肤神经纤维的密度。PQA-18（4 mg kg）还在大鼠小肠移植模型中显著提高了移植物的存活率。

IRAK-1-4 Inhibitor I 是一种IRAK1 4双重抑制剂，其IC50分别为 0.2 μM 和 0.3 μM。

Clerodendrin (Apigenin-7-O-glucuronopyranosyl(1-2)-glucuronopyranoside) 是一种从 Clerodendron trichotomm 的叶子中分离出一种新的新齿状二萜类化合物，是萝卜锯蝇 Athalia rosae ruficornis 的摄食刺激剂。Clerodendrin 是一种白介素-4 (IL-4) 抑制剂和 β-己糖氨基苷酶 (Hex) 抑制剂。

CC-90005 is a potent, selective and orally active inhibitor of protein kinase C-θ (PKC-θ), with an IC50 of 8 nM. CC-90005 shows selectivity for PKC-θ over PKC-δ (IC50=4440 nM). CC-90005 can inhibit T cell activation by IL-2 expression[1]. CC-90005 shows the exquisite selectivity of CC-90005, with IC50s for all other family members of >3 μM[1].CC-90005 is a moderate inhibitor of both CYP2C9 (IC50=8 μM) and CYP2C19 (IC50=5.9 μM) in human liver microsomes[1].CC-90005 inhibits IL-2 expression in LRS_WBC human PBMCs, with an IC50 of 0.15 μM[1].CC-90005 (1-10 μM; 24 h) inhibits T cell proliferation in PBMCs by 51% at 1 μM and 88% at 3 μM[1]. CC-90005 (3-30 mg kg; p.o. twice daily for 4 days) significantly reduces the popliteal lymph node (PLN) size in a model of chronic T cell activation[1].CC-90005 (100 mg kg; a single p.o.) significantly inhibits plasma and spleen IL-2 release by 51 and 54%, respectively[1].CC-90005 exhibits reasonable oral bioavailability (66 and 46%) and Cmax (1.18 and 1.2 μM) following oral administration (10 and 3 mg kg) in rat and dog, respectively[1].CC-90005 exhibits the mean residence time (0.52 and 2.0 h), CL (69.1 and 20.5 mL min kg) and Vss (2.11 and 2.44 L kg) following intravenous administration (2 and 1 mg kg) in rat and dog, respectively[1]. [1]. Papa P, et, al. Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005. J Med Chem. 2021 Aug 26;64(16):11886-11903.

T-5342126 is a toll-like receptor 4 (TLR4) antagonist.1It reduces LPS-induced production of nitric oxide (NO) in RAW 264.7 cells (IC50= 27.8 μM), as well as decreases LPS-induced IL-8, TNF-α, and IL-6 production in isolated human whole blood (IC50s = 110.5, 315.6, and 318.4 μM, respectively). T-5342126 (82 mg kg) reduces ethanol intake and the abundance of ionized calcium-binding adapter molecule 1 (Iba1), a marker of microglial activation, in the central nucleus of the amygdala in ethanol-dependent mice.2 1.Chavez, S.A., Martinko, A.J., Lau, C., et al.Development of β-amino alcohol derivatives that inhibit toll-like receptor 4 mediated inflammatory response as potential antisepticsJ. Med. Chem.54(13)4659-4669(2011) 2.Bajo, M., Montgomery, S.E., Cates, L.N., et al.Evaluation of TLR4 inhibitor, T5342126, in modulation of ethanol-drinking behavior in alcohol-dependent miceAlcohol Alcohol.51(5)541-548(2016)

Givinostat (ITF-2357) is a HDAC inhibitor with an IC50 of 198 and 157 nM for HDAC1 and HDAC3, respectively. Givinostat (ITF2357) suppresses total LPS-induced IL-1β production robustly compared with the reduction by ITF3056. At 25, 50, and 100 nM, Givinostat reduced IL-1β secretion more than 70%. Givinostat (ITF-2357) suppresses the production of IL-6 in PBMCs stimulated with TLR agonists as well as the combination of IL-12 plus IL-18. IL-6 secretion decreases to 50% at 50 nM Givinostat, but at 100 and 200 nM, there is no reduction[1]. As shown by the CCK-8 assay, Givinostat (ITF-2357) inhibits JS-1 cell proliferation in a concentration-dependent manner. Treatment with Givinostat ≥500 nM is associated with significant inhibition of JS-1 cell proliferation (P<0.01). Also, the cell inhibition rate significantly differs between the group cotreated with Givinostat ≥250 nM plus LPS and the group without LPS treatment (same Givinostat concentration) (P<0.05)[2]. Givinostat (ITF2357) at 10 mg kg is used as a positive control and, as expected, reduced serum TNFα by 60%. Strikingly, pretreatment of ITF3056 starting at 0.1 mg kg significantly reduces the circulating TNFα by nearly 90%. To achieve a significant increase in serum IL-1β production, a higher dose of LPS is injected (10 mg kg), and blood is collected after 4 h. Similarly, when pretreated with lower doses of Givinostat (ITF-2357) (1 or 5 mg kg), there is a 22% reduction for 1 mg kg and 40% for 5 mg kg[1]. [1]. Li S, et al. Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo. J Biol Chem. 2015 Jan 23;290(4):2368-78. [2]. Wang YG, et al. Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation. World J Gastroenterol. 2015 Jul 21;21(27):8326-39. [3]. Leoni F, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005 Jan-Dec;11(1-12):1-15.

p38 MAPK inhibitor (IC50 = 0.38 μM). Inhibits the release of IL-1β and TNF-α in a peripheral blood mononuclear cell (PBMC) assay (IC50 values are 0.039 and 0.16 μM respectively). Laufer et al (2003) Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes. J.Med.Chem. 46 3230 PMID:12852754 |Kammerer et al (2007) Pharmacokinetics of ML3403 ({4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-(1-phenylethyl)-amine), a 4-pyridinylimidazole-type p38 mitogen-activated protein kinase inhibitor. Drug Metab.Dispos. 35 875 PMID:17344341

Interleukin-2-inducible T cell kinase (ITK) is a non-receptor tyrosine kinase expressed in T cells, NKT cells and mast cells which plays a crucial role in regulating the T cell receptor (TCR), CD28, CD2, chemokine receptor CXCR4, and FcepsilonR-mediated signaling pathways. ITK inhibitors can be used for the treatment of inflammation and immune-mediated disorders. ITK inhibitor (N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy-phenyl]thio]thiazol-2-yl]-4-(N-1,2-dimethylpropylaminomethyl)benzamide) is the analogue of BMS-509744, which can potently and selectively inhibit Itk kinase activity. In vitro: BMS-509744 could reduce TCR-induced functions including PLCγ1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells [1]. In vivo: BMS-509744 suppressed the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma [1]. Clinical trial: Up to now, both BMS-509744 and ITK inhibitor is still in the preclinical development stage.

LDN 0088050 is selectivity adipocyte fatty acid binding protein (AFABP, FABP4) inhibitor with Ki values of 0.29 and 1.3 μM for FABP4 and FABP3, respectively. LDN 0088050 binds to FABP4 with a Kd of 2.05 μM[1]. Ki: 0.29 μM (FABP4), 1.3 μM (FABP3)[1]Kd: 2.05 μM (FABP4)[1] LDN 0088050 significantly inhibits LPS-induced expression of both TNFα and IL-6 in RAW264.7 cells[1]. [1]. Zhou Y, et al. The discovery of novel and selective fatty acid binding protein 4 inhibitors by virtual screening and biological evaluation. Bioorg Med Chem. 2016 Sep 15;24(18):4310-4317.

JC-171 is a selective NLRP3 inflammasome inhibitor, with an IC50 of 8.45 μM for inhibiting LPS ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages[1]. JC-171 (0-100 μM) blocks NLRP3 inflammasome activation and IL-1β production in primary macrophages dose dependently[1]. Cell Viability Assay[1] Cell Line: J774A.1 murine macrophage cells JC-171 treatment delays the progression and reduces the severity of experimental autoimmune encephalomyelitis (EAE) in mouse[1]. Animal Model: Mice immunized subcutaneously with 200 μg Myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide emulsified in Complete Freund's Adjuvant (CFA) on day 0 followed by injection of 200 ng of pertussis toxin. [1]. Chunqing Guo, et al. Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis. ACS Chem Neurosci. 2017 Oct 18;8(10):2194-2201.

IRAK4-IN-1 是白细胞介素-1 受体相关激酶 4 抑制剂(IC50:7 nM)。

AS2444697 是一种口服有效的IRAK-4抑制剂，IC50为 21 nM。它对人和大鼠 IRAK-4 活性具有抑制作用。它通过抗炎作用表现出肾脏保护作用。

IRAK inhibitor 1 是IRAK-4抑制剂(IC50:216 nM)，微弱抑制 JNK-1 (IC50:3.801 μM)和 JNK-2(IC50>10 μM)。

IRAK inhibitor 6 是白细胞介素-1受体相关激酶-4的抑制剂(IC50:160 nM)。

IRAK4-IN-7 (CA-4948) 是白介素 1 受体相关激酶 4 (IRAK4) 的选择性抑制剂，口服有活性。它可用于研究癌症以及炎症疾病。

HS-243 是 IRAK-4 和 IRAK-1 的抑制剂，IC50 分别为 20 和 24 nM。 HS-243 显示出抗炎和抗癌活性。

Theophylline (1,3-Dimethylxanthine) sodium glycinate 是一种有效的磷酸二酯酶 (PDE) 抑制剂，可抑制 PDE3 活性以松弛气道平滑肌。Theophylline sodium glycinate 可用于研究哮喘和慢性阻塞性肺疾病 (COPD) 。Theophylline sodium glycinate 也是一种腺苷受体拮抗剂和组蛋白脱乙酰酶 (HDAC) 激活剂。 Theophylline sodium glycinate 通过增加 IL-10 和抑制 NF-κB 的核输入而具有抗炎活性。Theophyllin sodium glycinate 可诱导细胞凋亡。

PF-07038124是 PDE4 的抑制剂。PF-07038124 对 PDE4B2 的 IC50值为0.5 nM。PF-07038124 对IFNγ、IL-4 和 IL-13具有抑制活性，IC50值分别为 1.06、4.1 和125 nM。

JAK-IN-24 是一种 JAK 抑制剂，在 4 μM 或 1 mM ATP 存在时，IC50分别为 0.534 和 24 nM。JAK-IN-24 还抑制 PBMCIL-15诱导的 STAT5磷酸化，IC50为 86.171 nM。