Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.

The identification of clinical candidate LY3522348 (compound ) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient ()-2-(2-methylazetidin-1-yl)-6-(1-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile ().

Caspase-8 Variant G Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Aggressive Behavior.

Objective: Fibroblast-like synoviocytes (FLS) play a pivotal role in rheumatoid arthritis (RA) by contributing to synovial inflammation and progressive joint damage. An imprinted epigenetic state is associated with the FLS aggressive phenotype. We identified CASP8 (encoding for caspase-8) as a differentially marked gene and evaluated its pathogenic role in RA FLSs.

Utilization of peptide phage display to investigate hotspots on IL-17A and what it means for drug discovery.

To date, IL-17A antibodies remain the only therapeutic approach to correct the abnormal activation of the IL-17A/IL-17R signaling complex. Why is it that despite the remarkable success of IL-17 antibodies, there is no small molecule antagonist of IL-17A in the clinic? Here we offer a unique approach to address this question. In order to understand the interaction of IL-17A with its receptor, we combined peptide discovery using phage display with HDX, crystallography, and functional assays to map and characterize hot regions that contribute to most of the energetics of the IL-17A/IL-17R interaction.