Abstract
Numerical taxonomy and pattern recognition analysis offer powerful tools that can greatly reduce the information burden of multiple-assay screening programs. These methods can be used to rationally design prescreens, identify assays with similar chemical response patterns, select reporter assays for chemical response groups, evaluate drug selectivity, and predict a drug's likely mechanism of action. When combined with assays designed to identify lead compounds with characteristics likely to cause failure at a later and more expensive stage of development, a simple 3-stage primary discovery process consisting of a rational prescreen, reporters, and clinical failure assay can reduce the number of required culture wells by more than 20-fold and can eliminate all but 1–2 drugs per 1,000 tested as leads for further evaluation and development.
Highlights
The extraordinary volume of data generated by high throughput screening has shifted the bottlenecks in drug discovery from compound acquisition and screening to the management and analysis of data
How can biological data be used to make the screening process smaller, simpler, faster, and cheaper? And how can biological data be used to better prioritize lead compounds for further development? Numerical taxonomy and pattern recognition offer powerful tools for addressing these questions, and can greatly reduce the information burden of multi-assay screening programs
Do we need to screen against all of them? Or, is it possible that some cancers might be similar enough to one another in their chemical response patterns that a single assay might serve as a reporter for an entire group of cell lines?
Summary
The extraordinary volume of data generated by high throughput screening has shifted the bottlenecks in drug discovery from compound acquisition and screening to the management and analysis of data. The worst behaving reporter line displayed an accuracy of more than 80% at SE values of 40 or greater These findings indicate that single reporter assays can reflect the behavior of an entire chemical response group with reasonable accuracy, and the use of reporter assays can greatly reduce the screening burden of multi-assay screening programs. With cell-based screening, a clinical failure assay combined with a rational prescreen and response group reporters can eliminate all but 1-2 drugs per 1,000 tested as leads for further evaluation and development. Of three stages: [1] an initial prescreen of two cell lines with single high-dose testing; [2] a selective toxicity screening panel in which test samples are screened in dose-response mode against six reporter lines; and [3] a long term recovery assay. They provide a simple method for presenting complicated data in a manner that is understood and which visually highlights patterns of differential sensitivity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: JALA: Journal of the Association for Laboratory Automation
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
