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L6H21 is an inhibitor of myeloid differentiation 2 (MD-2), also known as lymphocyte antigen 96 (LY96).1 It binds to MD-2 (Kd = 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

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 sepsisBr. 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 metastasisInt. 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 ratsBiochem. Biophys. Acta Mol. Basis Dis1868(2)166301(2021)

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