molecules of the month

The Takeda GPR139 agonist, TAK-041, is a CNS-penetrant GPCR agonist being explored for schizophrenia symptoms and is an interesting example of a triazinone-containing clinical candidate. GPR139 is an orphan GPCR that’s highly expressed in the human habenula, which plays a major role in avoidance behavior. Lesions in the habenula cause deficits in social behavior and cognitive abilities, and GPR139 KO’s demonstrate behavior deficits related to SCZ. Jake Schwarz notes: “While GPCRs are highly druggable, the agonist route is fraught with peril. Full agonism rarely mimics the natural state of a healthy receptor, where the agonist is not constantly present at the receptor. Partial agonists and PAMs have enjoyed much more success.” This first-in-class molecule is a notable example of clinical development of a…