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Publication Abstract from PubMed

Toll-like receptors 7 and 8 (TLR7/8) are transmembrane receptors that recognize single-stranded RNA. Activation of these receptors results in immune cell stimulation and inflammatory cytokine production which is normally a protective host response. However, aberrant activation of TLR7/8 is potentially pathogenic and linked to progression of certain autoimmune diseases such as lupus. Thus, we hypothesize that an inhibitor that blocks TLR7/8 would be an effective therapeutic treatment. Prior efforts to develop inhibitors of TLR7/8 have been largely unsuccessful due to the challenge of producing a small molecule inhibitor for these difficult targets. Here, we report the characterization of M5049 and Compound 2, molecules which were discovered in a medicinal chemistry campaign to produce dual TLR7/8 inhibitors with drug-like properties. Both compounds showed potent and selective activity in a range of cellular assays for inhibition of TLR7/8 and block molecule synthetic ligands and natural endogenous RNA ligands such as microRNA and Alu RNA. M5049 was found to be potent in vivo and TLR7/8 inhibition efficaciously treated disease in several murine lupus models and, interestingly, was efficacious in a disease context where TLR7/8 activity has not previously been considered a primary disease driver. Furthermore, M5049 had greater potency in disease models than expected based on its in vitro potency and pharmacokinetic/pharmacodynamic properties. With preferential accumulation in tissues, and the ability to block multiple TLR7/8 RNA ligands, M5049 may be efficacious in treating autoimmunity and has the potential to provide benefit to a variety of patients with varying disease pathogenesis. Significance Statement We report discovery of a novel toll-like receptor 7 and 8 (TLR7/8) inhibitor (M5049), characterize its binding mode, potency/selectivity, pharmacokinetic and pharmacodynamic properties, and demonstrate its potential for treating autoimmune diseases in two mouse lupus models. TLR7/8 inhibition is unique in that it may block both innate and adaptive autoimmunity and thus we believe that M5049 has the potential to benefit patients with autoimmune diseases.

Discovery of M5049: A Novel Selective TLR7/8 Inhibitor for Treatment of Autoimmunity.,Vlach J, Bender AT, Przetak M, Pereira A, Deshpande A, Johnson T, Reissig S, Tzvetkov E, Musil D, Tahmassian-Morse N, Haselmayer P, Favre-Zimmerli S, Okitsu SL, Walsky RL, Sherer B J Pharmacol Exp Ther. 2020 Dec 16. pii: jpet.120.000275. doi:, 10.1124/jpet.120.000275. PMID:33328334^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.