VBY-825

**VBY-825** is a novel, reversible small-molecule inhibitor of cysteine cathepsins with high potency against cathepsins B (Ki(app) 330 pM), L (250 pM), S (130 pM), and V (250 pM), and lesser activity against cathepsins K (2.3 nM) and F (4.7 nM). It forms a reversible covalent hemiothioketal linkage with the active site cysteine and binds structural pockets of the enzymes. Originally discovered through structure-based drug design at Celera Genomics and further developed by Virobay Inc., it demonstrates good metabolic stability, acceptable solubility, and effective inhibition in intact cells (e.g., IC50 4.3 nM for cathepsin B in HUVECs). In preclinical models, subcutaneous administration (10 mg/kg/day) achieved sustained plasma levels for full enzyme inhibition, reduced tumor burden by 52% and tumor number by 33% in a RIP1-Tag2 mouse model of pancreatic islet cancer, and inhibited inflammation in models of gout, peritonitis, and arthritis.[1][2][3][11]