TAK-242

TAK 242 is a toll-like receptor 4 (TLR4) signaling inhibitor. Binds to intracellular domain of TLR4. Inhibits LPS-induced cytokine production in vitro (IC₅₀ values are 1.3, 1.3 and 3.2 nM for IL-6, TNFα and NO production).?TAK-242 binds to the TIR domain of TLR4 via Cys747,^[1] and inhibits MyD88 and TRIF-dependent pathway. Previous studies showed that TAK-242 prevented acute kidney injury and lung injury in LPS-injected sheep and mice. What’s more, TAK-242 has also been tested in a clinical trial of patients with sepsis and was found to be well tolerated. It is also researched to have the usage as a therapeutic strategy for endotoxemia-associated muscle weakness.^[2]

In vitro study demonstrated that TAK-242 disrupts the interactions of TLR4 with its adaptor molecules, TIRAP and TRAM. TAK-242 inhibited the association of TIRAP with TLR4 and the association of TRAM with TLR4. The inhibitory effect of TAK-242 may result from the direct action of TAK-242 on TLR4 without requiring the induction of intermediate gene expression or de novo protein synthesis. Moreover, strong evidence was provided that TAK-242 modulates the formation of the signaling complex containing the proximal elements in TLR4 signaling. TAK-242 inhibited TIRAP mediated NF-γB activation and TRAM-mediated NF-γB and ISRE activation in the presence of TLR4/MD-2. In addition, TAK-242 also inhibited LPS-induced NF-γB and ISRE activations in HEK293-hTLR4/MD2-CD14 cells. These results indicated that TAK-242 impairs the ability of TLR4 to associate with adaptor molecules and blocks subsequent signal transduction.^[1]

In vivo experiments indicated that TAK-242 effectively reduced the severity of acute liver failure and increased the survival rate of FH mice. Mechanistically, the hepatoprotective effect of TAK-242 was related to inhibiting inflammation, reducing oxidative stress, and increasing the proportion of MDSCs. Results suggested that TAK-242 is a potent TLR4 inhibitor and would be a potential drug to protect against acute liver failure.^[3]

References:
[1]. Matsunaga N, et al. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol. 2011 Jan;79(1):34-41.
[2]. Ono Y, et al. TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice. Sci Rep. 2020 Jan 20;10(1):694.
[3]. Wang H, et al. Toll-like Receptor 4 Inhibitor TAK-242 Improves Fulminant Hepatitis by Regulating Accumulation of Myeloid-Derived Suppressor Cell. Inflammation. 2021 Apr;44(2):671-681.

TAK 242 是一种 Toll 样受体 4 (TLR4) 信号转导抑制剂。结合 TLR4 的细胞内结构域。在体外抑制 LPS 诱导的细胞因子产生（IL-6、TNFα 和 NO 产生的 IC₅₀ 值为 1.3、1.3 和 3.2 nM）。 TAK-242 通过 Cys747^[1] 与 TLR4 的 TIR 结构域结合,并抑制 MyD88 和 TRIF 依赖性通路。先前的研究表明,TAK-242 可预防注射 LPS 的绵羊和小鼠的急性肾损伤和肺损伤。此外,TAK-242 还在脓毒症患者的临床试验中进行了测试,发现耐受性良好。还研究了将其用作内毒素血症相关肌肉无力的治疗策略。^[2]

体外研究表明,TAK-242 破坏了 TLR4 与其衔接分子 TIRAP 和 TRAM 的相互作用。 TAK-242 抑制 TIRAP 与 TLR4 的结合以及 TRAM 与 TLR4 的结合。 TAK-242 的抑制作用可能源于 TAK-242 对 TLR4 的直接作用,而不需要诱导中间基因表达或蛋白质从头合成。此外,提供了强有力的证据表明 TAK-242 调节包含 TLR4 信号转导中近端元件的信号转导复合物的形成。 TAK-242 在 TLR4/MD-2 存在的情况下抑制 TIRAP 介导的 NF-γB 激活和 TRAM 介导的 NF-γB 和 ISRE 激活。此外,TAK-242 还抑制 HEK293-hTLR4/MD2-CD14 细胞中 LPS 诱导的 NF-γB 和 ISRE 激活。这些结果表明,TAK-242 削弱了 TLR4 与衔接分子结合的能力,并阻断了后续的信号转导。^[1]

体内实验表明,TAK-242 可有效降低急性肝衰竭的严重程度并提高 FH 小鼠的存活率。从机制上讲,TAK-242 的保肝作用与抑制炎症、减少氧化应激和增加 MDSCs 的比例有关。结果表明,TAK-242 是一种有效的 TLR4 抑制剂,有望成为预防急性肝衰竭的潜在药物。^[3]