Tyrosine kinase 2 (TYK2) is one of the four members of the Janus (JAK) family of kinases, which also includes JAK1, JAK2 and JAK3. JAK kinase hetero-, and to a lesser extent homo, pairs play a key role in signal transduction of cytokines which signal through the JAK- Signal and Transduction of Transcription (STAT) pathway. TYK2 is important in IL-23 and IL-12 signaling where it pairs with JAK2, and Type I interferon signaling where it pairs with JAK1. Genome-wide association studies have associated TYK2 loss of function loci with a number of auto-immune diseases including Crohn’s disease, ulcerative colitis, psoriasis, systemic lupus erythematosus, and, rheumatoid arthritis. The pharmacological profile of a selective TYK2 kinase inhibitor provides an opportunity to address a number of auto-immune diseases with a differentiated profile.<br/><br/>In this presentation we describe the discovery of an ATP competitive pyrazolopyrazinyl series of selective TYK2 inhibitors. The target profile and balanced selectivity against JAK2, was established through understanding of PK/PD relationships developed from our clinical experience. Through a structurally enabled program a scaffold hopping effort lead to several Type 1 kinase hinge designs and a preferred lead template. Further potency optimization involved leveraging P-loop engagement and simulated water thermodynamics. ADME properties in general in the program were favorable, however issues with non-P450 clearance pathways were identified, and a successful solution will be described. This effort led to the identification of PF-06826647 a potent and selective inhibitor of TYK2 which is currently in Phase 1 clinical studies.

Discovery of the TYK2 selective inhibitor PF-6826647 for the treatment of Crohn’s disease, and other autoimmune conditions

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.