Method for high-throughput screening of compounds and combinations of compounds for discovery and quantification of actions, particularly unanticipated therapeutic or toxic actions, in biological systems

Abstract

The invention enables high-throughput screening of compounds in living systems to detect unanticipated or unintended biological actions. The invention also allows for screening, detection, and confirmation of new indications for approved drugs. Screening and detection of toxic effects of compounds also can be achieved by using the methods of the invention. The methods comprise administering isotope-labeled substrates to a living system so that the label is incorporated into molecules in a manner that reveals flux rates through metabolic pathways thought to be involved in a disease. Comparisons between living systems exposed to compounds and living systems not so exposed reveals the effects of the compounds on the flux rates through the metabolic pathways. Combinations or mixtures of compounds can be systematically screened to detect unanticipated or unintended biological actions, including synergistic actions, in the same manner.

Description

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 525,261 filed Nov. 25, 2003, the disclosure of which is incorporated herein by referenced in its entirety.FIELD OF THE INVENTION

[0002] The invention relates to methods for screening compounds, combinations of compounds, or mixtures of compounds (i.e., drugs and drug candidates, including chemical entities, whether new or known, and biological factors, whether new or known) for actions in biological systems. The disclosed methods measure and quantify molecular flux rates through metabolic pathways (synthesis and breakdown or input and removal rates from pools of molecules) in vivo as targets of drug action. The disclosed methods are capable of high-throughput, large-scale, automated applications. The methods are particularly applicable to detecting and establishing unanticipated or unintended actions of drugs or drug candidates during drug discovery, d...

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