New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space

• Published in: Bioorganic & medicinal chemistry letters 2017-12, Vol.27 (24), p.5373-5377
• Main Authors: Brethon, Anne, Chantalat, Laurent, Christin, Olivier, Clary, Laurence, Fournier, Jean-François, Gastreich, Marcus, Harris, Craig S., Isabet, Tatiana, Pascau, Jonathan, Thoreau, Etienne, Roche, Didier, Rodeschini, Vincent
• Format: Article
• Language: English
• Subjects: 3D fragments; 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemical synthesis; 4-Butyrolactone - chemistry; 4-Butyrolactone - metabolism; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - metabolism; Binding Sites; Biological Products - chemistry; Biological Products - metabolism; Caspase 1 - chemistry; Caspase 1 - metabolism; Caspase Inhibitors - chemistry; Caspase Inhibitors - metabolism; Caspase-1; Crystallography, X-Ray; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - metabolism; Docking; Hydrogen Bonding; Inhibitory Concentration 50; Molecular Conformation; Molecular Docking Simulation; Natural product; Protein Structure, Tertiary; Scaffold hopping
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.11.015

[Display omitted] Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.