The Janus kinases (JAKs) are a family of intracellular tyrosine kinases which mediate the signal transduction of a number of cytokines and play a critical role in both innate and adaptive immunity as well as hematopoiesis. They are attractive targets for autoimmune diseases. JAK inhibitors which are non-selective within the JAK family and inhibit JAK2, which mediates EPO and TPO signaling, have the potential to induce anemia or thrombocytopenia. A JAK1 selective inhibitor may recapitulate the efficacy of non-JAK selective inhibitors in the treatment of immune disorders and mitigate the risk of JAK2 mediated hematopoietic effects.<br/>Data obtained from tofacitinib in RA clinical trials and also preclinical models was used to understand the relative inhibition profiles of JAK1 vs JAK2 by tofacitinib has allowed us to project a minimum selectivity required to avoid JAK2 mediated hematopoietic effects.<br/>Using kinase and cellular assays we identified a JAK1 selective series from our compound file. Robust crystallographic data enabled us to build a structural hypothesis for the JAK1 selectivity of our lead series. Through iterative medicinal chemistry, structure based drug design and use of in-house lead transformation tools we identified PF-04965842, a potent and selective JAK1 inhibitor which possessed a good preclinical PK profile and demonstrated efficacy in the rat AIA model of arthritis. PF-04965842 was advanced into development for the treatment of autoimmune diseases. Following the successful completion of a Phase 1 safety and tolerability trial the compound was advanced into a Ph2 PSO study.

Identification of selective JAK1 inhibitors for treatment of autoimmune diseases

251st National Meeting (2016)

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