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The toll-like receptors (TLRs) are integral to the innate immune system, serving as pattern recognition receptors for the early detection of molecular signatures presented by pathogenic sources such as bacteria and viruses. The TLRs can also be activated by endogenous ligands released from stressed or damaged cells. TLR7 and TLR8 are endosomally-localized members of the TLR family that respond to single-stranded RNA by recruitment of the cytosolic adaptor protein MyD88 and engagement of IRAK1/4. Subsequent downstream activation of the NFκB and IRF pathways leads to induction of pro-inflammatory cytokines and production of type-I interferons respectively. Undesired activation of TLR7/8 via self-motifs is believed to be a driver of lupus and other autoimmune disorders and has been implicated in the development of steroid resistance in some patients. In our search for antagonists of endosomal TLRs, small molecule hits originating from high throughput screening were optimized through structure-based design, aided by X-ray co-crystallographic structures. This presentation will detail those efforts, which culminated in the identification of afimetoran as a potent and selective dual antagonist of TLR7/8. Afimetoran demonstrated excellent pharmacokinetic profiles in non-clinical species and was profiled in MRL/lpr and NZB/W mouse models of lupus, where it was highly effective as monotherapy treatment at controlling disease and even reversing the signs of established disease. Combination of afimetoran with prednisolone showed improved results relative to either monotherapy in mouse lupus models as well as in human blood assays measuring inhibition of TLR7 or TLR8 responses. With successful completion of Phase I studies revealing a favorable human pharmacokinetic and pharmacodynamic profile, afimetoran was advanced into clinical evaluation in patients with cutaneous lupus (CLE) or systemic lupus (SLE).
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