PF-06651600, a dual JAK3/TEC family kinase inhibitor

PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity towards JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinomehave a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TECkinase family including BTK, BMX, ITK, RLK and TECand are also inhibited by PF-06651600. Preclinical data demonstrates that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TECkinases. Based on the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areataand vitiligo, the dual activity of PF-06651600 towards JAK3 and the TECkinase family may provide a beneficial inhibitory profile for ...