Discovery of an Orally Available Janus Kinase 3 Selective Covalent Inhibitor

JAK family kinases
are important mediators of immune cell signaling
and Janus Kinase 3 (JAK3) has long been indicated as a potential target
for autoimmune disorders. Intensive efforts to develop highly selective
JAK3 inhibitors have been underway for many years. However, because
of JAK3’s strong binding preference to adenosine 5′-triphosphate
(ATP), a number of inhibitors exhibit large gaps between enzymatic
and cellular potency, which hampers efforts to dissect the roles of
JAK3 in cellular settings. Using a targeted covalent inhibitor approach,
we discovered compound 32, which overcame ATP competition
(1 mM) in the enzymatic assay, and demonstrated significantly improved
inhibitory activity for JAK3-dependent signaling in mouse CTLL-2 and
human peripheral blood mononuclear cells. Compound 32 also exhibited high selectivity within the JAK family and good pharmacokinetic
properties. Thus, it may serve as a highly valuable tool molecule
to study the overlapping roles of JAK family kinases in complex biological
settings. Our study also suggested that for covalent kinase inhibitors,
especially those targeting kinases with low Km ATP values, the reversible interactions between molecules
and proteins should be carefully optimized to improve the overall
potency.