Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO.

GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens.

Characterisation of a K390R ITK kinase dead transgenic mouse--implications for ITK as a therapeutic target.

Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells and this has prompted significant efforts to discover ITK inhibitors for the treatment of allergic disease. However, ITK is known to have functions outside of its kinase domain and in general kinase knockouts are often not good models for the behaviour of small molecule inhibitors.