AMG-47a

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. AMG-47 is one of two optimized chemical compounds that has been shown to be extremely effective in vivo and in vitro in inhibiting Lck as well as a number of other receptor tyrosine kinases. In an anti-CD3/ IL-2 mouse model system AMG-47 has been shown to be effective in inhibiting the Lck mediated anti-inflammatory activity (ED50 11 mg/kg; 630nM) in vivo. In multiple other in vitro assays, AMG-47 exhibits subnanomolar inhibition against Lck, and low (< 10nM) inhibition against other hard to inhibit kinases such as KDR and SRC and MAPK α (p38α). Moreover at slightly higher doses but well under 10µM, AMG-47 effectively inhibits the JNK family of kinases including TYK2 at ~ 1.2µM.