Graphical and Numerical Methods Using Concentration-Response Profiles in Drug Discovery

• Activity Number: 350
• Type: Contributed
• Date/Time: Tuesday, August 5, 2014 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Patrick Edmonds*+ and Jo A. Wick and G. Sitta Sittampalam and Ajit Jadhav
• Companies: University of Kansas Medical Center and University of Kansas Medical Center and NIH/NCATS and NIH/NCATS
• Keywords: Concentration-Response ; Genomics ; qHTS ; Simulation

Abstract

The number of cancer drugs available for development is increasing, but this increase is limited by finite resources. The potential for improving efficiency is highest in early phases of discovery, thus developing a reliable method for predicting the activity of new chemical entities (NCEs) from preclinical data could have a substantial impact. The NIH Chemical Genomics Center has developed a quantitative high-throughput screening (qHTS) approach that extends HTS to derive the concentration-response profile of a compound during primary screening and IC50 or EC50 potency values. We developed several graphical and quantitative methods using qHTS to further differentiate and rank order NCEs based on area under the curve (AUC) that could identify NCEs that have greater potential of success in future stages of development. Methods are demonstrated using datasets investigating potentiation of the cytotoxicity of methyl methansulfonate (MMS) in SF767 cells. AUC is calculated from percent cell-killing in the presence and absence of MMS over a consistent range of concentrations. Simulation studies are used to assess the performance of AUC in differentiating and ranking compound curves.