Gang Yao
Drug Design and Selection, Medicinal Science & Technology, GlaxoSmithKline
200 Cambridge Park Drive, Cambridge, Massachusetts, 02140, USA

The JAK-family kinases, including TYK2, are unique in that they possess an ATP-binding JH2 domain in addition to a functional JH1 domain. JH2 ligand are found to negatively regulate activation of JH1 kinase domain. Inhibition of the JH2 domain may offer an unique opportunity to modulate the TYK2 kinase activity with high kinome selectivity.

This talk will describe the structure based optimization of a TYK2 pseudokinase inhibitor identified from a DNA encoded library. The binding mode of the hit molecule was confirmed by X-ray crystallography. Optimization of the initial hit led to the identification of a chemical series with exceptional kinome selectivity, inhibiting the pro-inflammatory cytokines IL-12 and IL-23 whilst sparing JAK2-mediated EPO signaling.

Interleukin-1 Receptor Associated Kinase 4 (IRAK4), is a serine/threonine kinase in the IL-1 receptor and toll-like receptor pathways and is recognized as important in innate immunity. Inhibition of IRAK4 is predicted to be beneficial in the treatment of a number of inflammatory diseases which has led to intense effort across the pharmaceutical industry to identify potent and selective inhibitors suitable for clinical study. The presentation will describe the discovery, structure and profile of clinical candidate PF-06650833 from Pfizer’s IRAK4 project.

Clinical candidate PF-06650833 arose from hits from an NMR-based fragment screen of the Pfizer Global Fragment library. Lead optimization of weakly active fragment hits, by applying structure- and property-based medicinal chemistry design strategies, led to a significant increase in IRAK4 potency and the discovery of a potent, efficient series of IRAK4 inhibitors with broad kinome selectivity and good pharmacokinetic properties. This work culminated in the discovery of PF-06650833 as a potential first-in-class IRAK4 inhibitor for the treatment of inflammatory disease.