Within the innate immune system, key components include several families of pattern recognition receptors (PRRs), including the Toll-Like Receptor (TLR) family. These PRRs recognize pathogen-associated molecular patterns (PAMPs) from microbial sources, and danger-associated molecular patterns (DAMPs) from stressed, damaged, or necrotic host cells. Endosomally localized TLR7, 8 and 9 respond to single-stranded (ss)RNA (TLR7/8) or unmethylated ssDNA (TLR9) and their aberrant activation by self-RNA/DNA contributes to the disease pathophysiology of systemic lupus erythematosus (SLE) and related autoimmune diseases by the production of cytokines (e.g. IL-6, IL-12, TNFα, IFNα) and B-cell activation. Inhibition of this undesired TLR7/8/9 activation is anticipated to offer therapeutic benefit for SLE patients. High throughput screening (HTS) of a compound collection led to the identification of a series of antagonists of TLR7/8/9 based on an indole template. This presentation will detail the in vitro and in vivo optimization of this series leading to the identification of compounds with excellent on-target potency and high efficacy in rodent models of lupus and other autoimmune disorders.

Discovery of small molecule antagonists of the toll-like receptors TLR7/8/9 for the treatment of lupus

2019 Fall National Meeting

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