The identification, characterization and optimization of small molecule probes of cysteine proteases: experiences of the Penn Center for Molecular Discovery with cathepsin B and cathepsin L.
During the pilot phase of the NIH Molecular Library Screening Network, the Penn Center for Molecular Discovery focused on a series of projects aimed at high throughput screening and the development of probes of a variety of protease targets. This review provides our medicinal chemistry experience with two such targets--cathepsin B and cathepsin L. We describe our approach for hit validation, characterization and triage that led to a critical understanding of the nature of hits from the cathepsin B project. In addition, we detail our experience at hit identification and optimization that led to the development of a novel thiocarbazate probe of cathepsin L.
Huryn
Donna M
DM
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA. Huryn@sas.upenn.edu
Smith
Amos B
AB
D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D057056:Cysteine Proteases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D015335:Molecular Probes / Q000032:analysis / Q000737:chemistry*
D015853:Cysteine Proteinase Inhibitors; D015335:Molecular Probes; D057056:Cysteine Proteases; D002401:Cathepsin B; D056668:Cathepsin L