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Recent Publications

Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

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.

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Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d] pyrimidin-4-yl) amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans

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. 

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Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences

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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