TY - JOUR T1 - Synthetic Small-Molecule Prohormone Convertase 2 Inhibitors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 617 LP - 625 DO - 10.1124/mol.108.051334 VL - 75 IS - 3 AU - Dorota Kowalska AU - Jin Liu AU - Jon R. Appel AU - Akihiko Ozawa AU - Adel Nefzi AU - Robert B. Mackin AU - Richard A. Houghten AU - Iris Lindberg Y1 - 2009/03/01 UR - http://molpharm.aspetjournals.org/content/75/3/617.abstract N2 - The proprotein convertases are believed to be responsible for the proteolytic maturation of a large number of peptide hormone precursors. Although potent furin inhibitors have been identified, thus far, no small-molecule prohormone convertase 1/3 or prohormone convertase 2 (PC2) inhibitors have been described. After screening 38 small-molecule positional scanning libraries against recombinant mouse PC2, two promising chemical scaffolds were identified: bicyclic guanidines, and pyrrolidine bis-piperazines. A set of individual compounds was designed from each library and tested against PC2. Pyrrolidine bis-piperazines were irreversible, time-dependent inhibitors of PC2, exhibiting noncompetitive inhibition kinetics; the most potent inhibitor exhibited a Ki value for PC2 of 0.54 μM. In contrast, the most potent bicyclic guanidine inhibitor exhibited a Ki value of 3.3 μM. Cross-reactivity with other convertases was limited: pyrrolidine bis-piperazines exhibited Ki values greater than 25 μM for PC1/3 or furin, whereas the Ki values of bicyclic guanidines for these other convertases were more than 15 μM. We conclude that pyrrolidine bis-piperazines and bicyclic guanidines represent promising initial leads for the optimization of therapeutically active PC2 inhibitors. PC2-specific inhibitors may be useful in the pharmacological blockade of PC2-dependent cleavage events, such as glucagon production in the pancreas and ectopic peptide production in small-cell carcinoma, and to study PC2-dependent proteolytic events, such as opioid peptide production. The American Society for Pharmacology and Experimental Therapeutics ER -