Drug discovery and target validation.

Abstract

Recent drug discovery has been driven largely by a genomics-based approach. This revolution in pharmaceutics is based on localized expression of either a novel gene or homologue of a known gene found in cDNA libraries made from normal versus diseased tissue. The choice and quality of cDNA library is critical for the success of this approach. Expression is normally verified at the cellular level by either immunocytochemistry or in situ hybridization. Activity of the recombinant protein in secondary cell-based assays allows highthroughput screens to be formulated to identify small-molecule effectors of this protein. More recently, a proteomics approach has also been incorporated into this process. This technology directly measures proteins whose expression is localized in disease tissue as the basis for cell-based screens to look for either activators or inhibitors, of this activity. The majority of screens are designed to look for inhibitors. Activity of small-molecules found by screening gives rise to pharmacokinetic studies and verification of activity in animal models of the disease. Structure-activity relationship (SAR) optimization of these small-molecules allows for suitable oral bioavailability and pharmacokinetics, resulting in compounds progressing from discovery to development. Based on these strategies, we have developed inhibitors of osteoclast-mediated bone resorption and are currently screening for bone anabolic agents. In addition, we have also developed small-molecule caspase inhibitors which prevent chondrocyte apoptosis and retain cell function in an attempt to find therapeutic agents to either prevent or treat osteoarthritis. These agents may well have utility in the treatment of temporomandibular joint diseases.