tlr 12

TLR7 agonist12 (example 20) 是一种针对惰性淋巴系统恶性肿瘤具有广泛抗肿瘤活性的TLR7激动剂及嘌呤核苷类似物。其抗癌机制主要通过抑制DNA合成和诱导细胞凋亡(apoptosis)来实现。

TLR7 8 agonist 12 (compound 9) 是一种 hTLR7 8 激动剂，其 EC50 值为 11 nM (hTLR7) 和 150 nM (hTLR8)，并且显示出免疫调节潜力。

CU-T12-9 是特异性 TLR1 2激动剂，可激活先天免疫系统和适应性免疫系统。它选择性激活 TLR1 2 异二聚体，可通过促进 TLR1 和 TLR2 二聚而激活 NF-κB 信号，引起下游 TNF-α、IL-10 和 iNOS 增加。

CU-CPT22 是 toll 样受体 1 和 2 蛋白复合物抑制剂，可阻断 Pam3CSK4诱导的 TLR1 2 激活，IC50值为 0.58 µM。 它与 TLR1 2 结合的合成三酰脂蛋白竞争，Ki 值为 0.41 µM。

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.