L6H21

L6H21 is an inhibitor of myeloid differentiation 2 (MD-2), also known as lymphocyte antigen 96 (LY96).¹ It binds to MD-2 (K_d = 33.3 µM in a cell-free assay) and inhibits the protein-protein interaction between MD-2 and toll-like receptor 4 (TLR4) in LPS-stimulated ECV304 cells. L6H21 (10 µM) decreases the migration of LPS-stimulated HCT116 colon cancer cells.² It inhibits LPS-induced increases in the production of TNF-α and IL-6 in mouse primary macrophages (IC₅₀s = 6.17 and 7.72 µM, respectively), as well as increases survival in a mouse model of LPS-induced sepsis.¹ L6H21 (40 mg/kg) increases cardiac levels of glutathione peroxidase 4 (GPX4) and decreases cardiac mitochondrial reactive oxygen species (ROS) in rats fed a high-fat diet.³

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1. Wang, Y., Shan, X., Chen, G., et al. MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis. Br. J. Pharmacol. 172(17), 4391-4405 (2015).

2. Rajamanickam, V., Yan, T., Xu, S., et al. Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis. Int. J. Biol. Sci. 16(8), 1288-1302 (2020).

3. Sumneang, N., Oo, T.T., Singhanat, K., et al. Inhibition of myeloid differentiation factor 2 attenuates cardiometabolic impairments via reducing cardiac mitochondrial dysfunction, inflammation, apoptosis and ferroptosis in prediabetic rats. Biochem. Biophys. Acta Mol. Basis Dis 1868(2), 166301 (2021).