Rapid, High Content Pharmacology
Steven J Brown, Imran B. Clark, Bala Pandi · Burger's Medicinal Chemistry and Drug Discovery · 2003
Abstract High‐throughput pharmacology will play an increasingly important role in drug development as companies strive to limit the likelihood that a compound will be removed from the market or fail phase II and III clinical trials because of unexpected side effects or toxicity. Identification of the correct compounds to advance from hit to lead‐compound candidate requires the determination of efficacy and evaluation of potential compound liabilities (solubility, adsorption, toxicity) and specificity of action. We propose that the characterization of the response of hit compounds against a broad panel of natural human cells will be very useful in making the correct selection. Because genes are not overexpressed in these cells, the signaling pathways are not altered by changes in protein stoichiometry. In addition, our cell bank has been genetically indexed and characterized for responses to known pharmacological agents and stored in a database. Thus, the pattern of functional responses (such as membrane potential, changes in intracellular calcium, cAMP etc.) obtained with test compounds can be compared with the known responses and gene expression, allowing for the ready identification of compounds with unexpected toxicities and effects. In addition, in vitro assays for evaluation of the adsorption and metabolism properties of compounds can be used to screen for compounds with drug‐like properties. These systems and methods provide high definition, content‐rich information about cellular responses and have sufficient throughput for use in screening hit compounds.