Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B.

Toll-like receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate ()-2-((2-amino-7-fluoropyrido[3,2-]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, ()-). Potent TLR8 agonism (IL-12p40 EC = 220 nM) and >100-fold TLR7 selectivity (IFN-α EC > 50 μM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:()- complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral ()- had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with ()-, supporting the clinical development of ()- for the treatment of CHB.