E6446 (hydrochloride)

E6446 is an antagonist of toll-like receptor 7 (TLR7) and TLR9 (IC₅₀s = 1.78 and 0.01 µM, respectively).¹ It is selective for TLR7 and TLR9 over TLR4 (IC₅₀ = 10.58 µM). E6446 inhibits IL-6 production induced by the TLR9 agonist CpG ODN2216 or TLR7 agonist RNA40 in isolated mouse bone marrow-derived dendritic cells (BMDCs) in a concentration-dependent manner. It prevents increases in left ventricle chamber size and cardiac fibrosis in a mouse model of heart failure induced by transverse aortic constriction when administered at a dose of 1.5 mg/animal.² E6446 (10 mg/kg) increases survival and reduces increases in right ventricular systolic pressure and hypertrophy in a rat model of pulmonary hypertension induced by the alkaloid monocrotaline (Item No. 16666).³ It has also been used to enhance the transfection efficiency of cell-penetrating peptides for the delivery of mRNA in vitro.⁴

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1. Lamphier, M., Zheng, W., Latz, E., et al. Novel small molecule inhibitors of TLR7 and TLR9: Mechanism of action and efficacy in vivo. Mol. Pharmacol. 85(3), 429-440 (2014).

2. Ueda, H., Yamaguchi, O., Taneike, M., et al. Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice. JACC Basic Transl. Sci. 4(3), 348-363 (2019).

3. Ishikawa, T., Abe, K., Ishikawa-Takana, M., et al. Chronic inhibition of toll-like receptor 9 ameliorates pulmonary hypertension in rats. J. Am. Heart Assoc. 10(7), e019247 (2021).

4. Bell, G.D., Yang, Y., Leung, E., et al. mRNA transfection by a Xentry-protamine cell-penetrating peptide is enhanced by TLR antagonist E6446. PLoS One 13(7), e0201464 (2018).