European collaboration seeks to eliminate barriers to hepatotoxicity tools

PARIS—To bring down one of the major remaining challenges to drug discovery—hepatotoxicity—Aureus Pharma has teamed with Budapest, Hungary-based ChemAxon; the Budapest University of Technology and Economics; and  Paris-based sanofi-aventis for a project called KnowTox. The goal of the project is to build a new knowledge base related to hepatotoxicity and to design related predictive tools to extend the value of the system.

 

Drug hepatotoxicity is a major threat during the drug development and marketing process, says Dr. Francois Petitet, director of life sciences at Aureus Pharma. "The recent example of severe adverse events with statins and the economic and social consequences of such failure highlights the need of assessing as early and accurately as possible the effect of drug candidates on hepatotoxicity," he notes, adding that even though some hepatotoxicity knowledge exists from preclinical and clinical experiences, data is scattered in numerous sources and cannot easily be accessed simultaneously.

 

In this project, Aureus Pharma brings its expertise in building chemical biology knowledge databases and sanofi-aventis provides toxicological experts from the pharmaceutical industry to validate the products. In Hungary, ChemAxon, a software solution provider, and the Budapest University of Technology and Economics will add their expertise in chemical reaction modeling to extend their existing software tools to deal with reactions and substrates involved in the metabolism of compounds. They are also working to develop predictive tools for hepatotoxicity.

 

"[These tools] will allow researchers access to previous failures and pertinent toxic alerts which will limit failure during the drug discovery process," Petitet predicts.

 

There are no plans at this point to add to functionality of the knowledge base or predictive tools outside of hepatotoxicity.

 

"It is hard to go beyond hepatotoxicity because it turns out this is the most difficult area of toxicity," says Dr. Miklos Vargyas, CSO at ChemAxon. "There are not really any predictive tools for hepatotoxicity. There are for other types of toxicity, but not for this troubling area."

 

ChemAxon has accomplished the first part of the project and Vargyas says the results are "quite promising thus far," with roughly 30 human metabolic reactions with predictions that turned out to be very accurate. In the second part of the project, the metabolic reactions will be expanded in scope to 300.

 

The metabolite prediction software is based on ChemAxon's Reactor program, a generic modeling engine that can be set up to work with various reaction libraries and which has already been released.