molecules of the year

The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist (LSN3318839) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. GLP-1 agonism is a well-established mechanism for treatment of diabetes, with most drugs being injectable peptides (glucagon or its derivatives). The starting point was identified from a 220k compound cell-based screen in the presence of GLP-1 peptide, and optimization of PK of prior lead LSN3160440 led to LSN3318839. Oral administration of LSN3318839 (30 mg/kg) results in a blood glucose lowering effect in animal models, which is additive with sitaglipin administration. It is the first characterized molecular glue for GPCRs with demonstrated in…