TAK-242

TAK-242 is an antagonist of toll-like receptor 4 (TLR4) with an IC₅₀ value of 0.68 µM in a secreted alkaline phosphatase (SEAP) assay.¹ It selectively binds to TLR4 over TLR1-3 and TLR5-10 when used at a concentration of 100 nM.² TAK-242 (1 µM) prevents the interaction of TLR4 with its adaptor proteins TIRAP or TRAM in HEK293 cells expressing the human receptors.² It inhibits IFN-γ- and LPS-induced production of nitric oxide (NO), TNF-α, IL-6, and IL-1β in isolated mouse peritoneal macrophages (IC₅₀s = 5.7-11 nM), as well as inhibits LPS-induced NETosis in isolated human neutrophils when used at concentrations ranging from 5 to 20 µM.^3,4 TAK-242 (0.3, 1, and 3 mg/kg) improves survival in a mouse model of septic shock induced by LPS.⁵

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1. Huang, J., Zhou, Z., Zhou, M., et al. Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout. Bioorg. Med. Chem. 26(8), 1653-1664 (2018).

2. Matsunaga, N., Tsuchimori, N., Matsumoto, T., 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. 79(1), 34-41 (2011).

3. Ii, M., Matsunaga, N., Hazeki, K., et al. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol. Pharmacol. 69(4), 1288-1295 (2006).

4. Khan, M.A., Farahvash, A., Douda, D.N., et al. JNK activation turns on LPS- and gram-negative bacteria-induced NADPH oxidase-dependent suicidal NETosis. Sci. Rep. 7(1), 3409 (2017).

5. Yamada, M., Ichikawa, T., Ii, M., et al. Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: Synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate. J. Med. Chem. 48(23), 7457-7467 (2005).