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Aureus, ChemAxon Partner with Sanofi-Aventis in $1.72M European Predictive Tox Database Project

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Eureka, a network of European R&D funding agencies, has awarded a research consortium €1.35 million ($1.72 million) to develop a database on drug-induced hepatotoxicity together with a suite of computational tools capable of predicting the toxicity of compounds and metabolites.

The two-year project, called KnowTox, is led by Paris-based database provider Aureus Pharma. Other partners include Budapest, Hungary-based cheminformatics firm ChemAxon, the Budapest University of Technology and Economics, and drug maker Sanofi-Aventis.

François Petitet, director of life sciences at Aureus, said that his firm submitted the initial proposal for the project because there are currently no comprehensive resources for hepatoxicity data, despite the increasing focus within pharma on safety issues.

Aureus has a growing family of biopharmaceutical databases, dubbed AurScope, that it has created by combing the scientific literature. Last March, the company introduced its first effort in the area of toxicity with AurScope hERG Channel, a database of published structure-activity relationships on hERG-ligand interactions related to cardiotoxicity. The company also sells databases with curated information on G-protein coupled receptors, ion channels, and ADME/drug-drug interactions.


Aureus selected cardiotoxicity as its first foray in this area because it has "a clear mechanism of action." Hepatotoxicity, on the other hand, is expected to be a bit more complex.

Petitet said that the company is seeing strong demand for toxicity data from pharmaceutical customers. Aureus selected cardiotoxicity as its first foray in this area, he said, because it has "a clear mechanism of action." Hepatotoxicity, on the other hand, is expected to be a bit more complex.

The project will require a clear understanding of metabolic pathways, for example, "because most of the metabolism is in the liver, and either the parent compound or the metabolites could be the origin of toxicity for the compound," Petitet said.

According to the KnowTox web site, the project partners will develop four separate products: A database structure "meeting the expectation of industrial experts who wanted to record their knowledge for use in the drug development process;" a database on drug-induced hepatotoxicity that will include chemical characteristics, detailed biological responses, and descriptors of the biological protocol used; data-mining software able to query the database; and a software tool capable of predicting metabolites and their hepatotoxicity.

Aureus will be responsible for designing the database structure, mining the literature for chemistry and biology data, and building the query software. Petitet said that Eureka projects encourage commercialization, so Aureus plans to market the database under its AurScope line once it is developed.

Sanofi-Aventis, meanwhile, will identify the scientific literature that Aureus should use in the project, and will also validate the structure and the content of the database. Scientists from the company will provide feedback on their needs for the query software and the hepatotoxicity database, and will also ensure that their proprietary hepatotoxiticy data can be integrated with that of the database.

Petitet said that Sanofi-Aventis will not be contributing any data to the effort. A Sanofi-Aventis scientist working on the project declined to comment for this article.

ChemAxon, which specializes in structure-property prediction tools, will help Aureus with the development of the database, but its main focus will be to develop the metabolite prediction software tool and the hepatotoxicity prediction software tool.

This would mark a departure for ChemAxon, which does not currently have any products in the ADMET area. Alex Allardyce, director of communications at the company, said that ADMET properties are "tricky" to forecast when compared with the types of properties that the company's software currently predicts, such as pKa, logP, logD, charge distribution, polarizability, H-bond acceptor/donor sites, and the like.

Allardyce said that the Eureka funding will alleviate some of the risk of tackling the challenging development task. The KnowTox project partners will provide metabolite and toxicity data that ChemAxon, in collaboration with Budapest University, can then integrate into a rule base to build predictive models.

The project appears to have arrived at an opportune time. As BioInform reported last week, pharmaceutical firms are beginning to view computational toxicology as an attractive alternative to expensive and time-consuming animal studies, particularly as the industry faces rising safety concerns [BioInform 05-12-06].

Aureus Pharma's Petitet declined to pin a number on the market opportunity for the fruits of the KnowTox project, but he said he thinks the database and predictive tools should have broad appeal. "The market will be anyone at an institution or in the pharmaceutical industry that is interested in toxicity of drugs, and specifically toxicity of the liver," he said.

— Bernadette Toner ([email protected])

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