1. Academic Validation
  2. Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity

Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity

  • J Pharmacol Exp Ther. 2021 Mar;376(3):397-409. doi: 10.1124/jpet.120.000275.
Jaromir Vlach 1 Andrew T Bender 2 Melinda Przetak 1 Albertina Pereira 1 Aditee Deshpande 1 Theresa L Johnson 1 Sonja Reissig 1 Evgeni Tzvetkov 1 Djordje Musil 1 Noune Tahmassian Morse 1 Philipp Haselmayer 1 Simone C Zimmerli 1 Shinji L Okitsu 1 Robert L Walsky 1 Brian Sherer 1
Affiliations

Affiliations

  • 1 EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Billerica, Massachusetts (J.V., A.T.B., M.P., A.P., A.D., T.J., E.T., N.T.M., S.F.Z., S.L.O., R.W., B.S.) and Merck KGaA, Darmstadt, Germany (S.R., D.M., P.H.).
  • 2 EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Billerica, Massachusetts (J.V., A.T.B., M.P., A.P., A.D., T.J., E.T., N.T.M., S.F.Z., S.L.O., R.W., B.S.) and Merck KGaA, Darmstadt, Germany (S.R., D.M., P.H.) andrew.bender@emdserono.com.
Abstract

Toll-like Receptor (TLR) 7 and TLR8 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 as a result of 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 synthetic ligands and natural endogenous RNA ligands such as MicroRNA and Alu RNA. M5049 was found to be potent in vivo as TLR7/8 inhibition efficaciously treated disease in several murine lupus models and, interestingly, was efficacious in a disease context in which 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. Because of its preferential accumulation in tissues, and 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: This study reports discovery of a novel Toll-like Receptor (TLR) 7 and TLR8 Inhibitor (M5049); characterizes its binding mode, potency/selectivity, and pharmacokinetic and pharmacodynamic properties; and demonstrates 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; thus, this study suggests that M5049 has the potential to benefit patients with autoimmune diseases.

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