Development of Selective Covalent Janus Kinase 3 Inhibitors

The
Janus kinases (JAKs) and their downstream effectors, signal transducer
and activator of transcription proteins (STATs), form a critical immune
cell signaling circuit, which is of fundamental importance in innate
immunity, inflammation, and hematopoiesis, and dysregulation is frequently
observed in immune disease and cancer. The high degree of structural
conservation of the JAK ATP binding pockets has posed a considerable
challenge to medicinal chemists seeking to develop highly selective
inhibitors as pharmacological probes and as clinical drugs. Here we
report the discovery and optimization of 2,4-substituted pyrimidines
as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909)
residue in JAK3. Investigation of structure–activity relationship
(SAR) utilizing biochemical and transformed Ba/F3 cellular assays
resulted in identification of potent and selective inhibitors such
as compounds 9 and 45. A 2.9 Å cocrystal
structure of JAK3 in complex with 9 confirms the covalent
interaction. Compound 9 exhibited decent pharmacokinetic
properties and is suitable for use in vivo. These inhibitors provide
a set of useful tools to pharmacologically interrogate JAK3-dependent
biology.