Peptidyl Arginine Deiminase 2 (PAD2) is a member of a class of enzymes which facilitate the conversion of arginine to citrulline, suspected to be involved in several autoimmune diseases. This report details the discovery and characterization of a novel inhibitor which binds at a unique allosteric site.
A large amount of resources in the pharmaceutical industry have been devoted to identifying selective inhibitors of JAK3, an important kinase in immune activation. JAK3 possesses a unique cysteine residue (Cys909) which is missing in the other three JAK family kinases (JAK1, JAK2, and TYK2), and which was used to target JAK3 with an acrylamide-based covalent inhibitor. This report details the discovery and optimization of PF-06651600, a potent and low-clearance compound with in vivo efficacy.
TYK2 is a member of the JAK family of kinases, controlling downstream signaling of both IL-12 and IL-23 receptors. Translation of efficacy from cellular to preclinical models is integral to the success of a drug discovery program. This report details the serendipitous discovery of a single amino acid difference (Ile--> Val at human position 960, mouse position 980) responsible for a dramatic dropoff in potency in the murine system. Using a V980I murine knock-in, we were able to restore activity in a mouse preclinical model, demonstrating the importance of understanding the translational pharmacology early in the drug discovery process.
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