JAK3-IN-11 (Compound 12), a potent, noncytotoxic, irreversible, orally active JAK3 inhibitor with IC 50 value of 1.7 nM, has excellent selectivity (>588-fold compared to other JAK isoforms), covalently bind to the ATP-binding pocket in JAK3. JAK3-IN-11 strongly inhibits JAK3-dependent signaling and T cell proliferation, is a promising tool for study autoimmune diseases.