Oxicity is critical to ensuring that only suitable drugs are put
Oxicity is critical to ensuring that only suitable drugs are put into clinical trials. Dale Johnson (Chiron Corporation, Emeryville, USA) presented computational approaches to the prediction of drug-induced toxicity. Kyle Kolaja (Iconix Pharmaceuticals, Mountain View, USA) explained the potential of the company’s DrugMatrix, a proprietary chemogenomics database that incorporates information from animal studies, gene-expression profiling, in vitro assays and literature sources. The power of the method was illustrated by the identification and use of kidney biomarkers as early predictors of nephrotoxicity. Stephen Durham (Bristol-Myers Squibb, Princeton, USA) and James McKim (CeeTox, Kalamazoo, USA) both described the benefits of early application of in vitro toxicology studies to identifying potential liabilities before substanOver the past two decades a number of alternative platforms for drug WP1066 site discovery have allowed the industry to go well beyond small-molecule and oligopeptide drugs. Recombinant proteins, monoclonal antibodies, gene therapy, antisense, RNAi, and aptamers each represent relatively unexplored frontiers for drug discovery. Antibodies, antisense and RNAi were the focus of a session entitled `Biologics’, which does not do justice to the enormous potential of these novel modalities. Napoleone Ferrara (Genentech, San Francisco, USA) recounted the odyssey-like discovery and development of Avastin, a non-immunogenic recombinant humanized monoclonal antibody (93 human, 7 mouse) that targets vascular endothelial growth factor (VEGF) and is now used as first-line treatment for metastatic colorectal carcinoma. Frank Bennett (ISIS Pharmaceuticals, Carlsbad, USA)Genome Biology 2005, 6:http://genomebiology.com/2005/6/7/Genome Biology 2005,Volume 6, Issue 7, ArticleBurley and Park 330.summarized the relative predictability of antisense oligonucleotides as therapeutic agents and their potential to improve efficacy and lower costs. For the uninitiated, not to mention those skeptics who recall the checkered past of antisense PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/28859980 approaches, he explained the multiple mechanisms by which oligonucleotides act on RNA and described how medicinal chemistry has improved their potency and pharmacokinetic properties, and lowered their cost. Finally, John Maraganore (Alnylam Pharmaceuticals, Cambridge, USA) discussed therapeutic applications of RNAi, as exemplified by an siRNA-based agent against respiratory syncytial virus (RSV) agent, which has good cell permeability and appropriate albumin binding, plasma half-life, and tissue distribution. The painstaking development process involves choosing the right sequence, modifying the oligonucleotide backbone to avoid nuclease digestion, and then conjugating it with cholesterol to improve both plasma half-life and biodistribution. The message from these three talks was clear. Biologics can offer superior validation, better pharmacokinetic properties, and more predictable toxicity profiles, which often mean a faster path to successful proofof-concept clinical trials. During this meeting, we learned a great deal about how different organizations are working to implement facets of Leslie Brown’s prescription to “use the right technology to find the right drug modulating the right target in the right patient”. It was made clear that genomic approaches to the problem are likely to bear considerable fruit over the next five years. Integration of diagnostic tools with predictive pharmacology and toxicology shoul.
