There is an acute need for the development of rapid techniques that can be used in the preclinical and early clinical phases of drug development to assess organ-specific toxicity of drugs and their human metabolites, as well as to predict the likelihood of adverse drug reactions that result from drug metabolism. To address these needs, Solidus Biosciences, Inc. is proposing to develop a proprietary Metabolizing Enzyme Toxicology Assay Chip (MetaChip TM) for high-throughput analysis of drug metabolism and toxicology, and metabolite profiling of drug candidates. The MetaChip TM combines human P450 biocatalysts with pharmacological screening to provide rapid identification of organ-specific drug toxicity, potential adverse drug interactions, and full metabolite profiling. This information is critical for the design of patient-specific treatment regimens, as well as for the identification of pharmacologically safe and effective lead compounds for advancement to clinical trials. The MetaChip TM technology employs human P450s to generate metabolites that are screened for cytotoxicity and cell growth inhibition to assess organ-specific toxicity, all in a high-throughput methodology.
The specific aims, and milestones, of this Phase I STTR proposal are to: 1. Incorporate human P450s, individually and in physiologically-relevant combinations, into sol-gel matrices and identify optimal formulation conditions for high catalytic activity and stability. Generate high-density arrays of P450s in sol-gel spots, up to 10,000 spots per standard microscope slide; 2. Perform rapid P450 inhibition assays on the MetaChip using known inhibitors of the different human P450s; 3. Culture human cells, including hepatocytes and kidney cells, in collagen gels and as cell monolayers that will enable in vitro cytotoxicity assays to be performed with cells growing in collagen gel spots overlaid directly on the sol-gel spots; 4. Demonstrate in situ metabolite synthesis and cytotoxicity testing on the MetaChip. The fully-developed MetaChip technology can be combined with other in vitro toxicology and metabolite profiling approaches that deal with ADME of xenobiotics, and therefore, will become an important tool in the development of in vitro models that mimic human metabolism.
