molecules of the month

Ritlecitinib: A deceptively simple structure hides a complex covalent drug discovery story Pfizer’s ritlecitinib (PF-06651600), a first-in-class, selective, oral covalent inhibitor of Janus kinase 3 (JAK3) and the TEC family of kinases, was recently FDA approved in June 2023 for the treatment of an autoimmune hair loss condition (severe alopecia areata). The molecule is derived from tofacitinib, an approved JAK1/3 inhibitor that Pfizer originally believed was a selective JAK3 inhibitor based on biochemical data, but turned out to be equally active against JAK1 in cellular contexts. Ritlecitinib derives its JAK-family kinase selectivity from covalent modification of a unique cysteine (C909) on JAK3, and is strongly active despite weak, micromolar binding affinity due to a relatively high kinetic rate of inactivation.…