Optimization of small molecule compounds by gene expression profiling: A systems biology approach to drug development.

2

Systems biology can be defined as the utilization of many different computational methods to gain a better understanding of complex biological systems. The approach can yield valuable information at every phase in the drug discovery process from the selection of genes and pathways as targets for high throughput screening, to lead compound series optimization. At Avalon pharmaceuticals, we have developed multiple transcriptional technologies to monitor the gene expression signatures of cells treated with small molecule compounds. The resultant data are integrated and interpreted through the use of several different computational tools and methods. Utilizing this approach, we have a better understanding of how complex biological systems respond to treatment with potential anti-cancer compounds and incorporate this understanding in devising and implementing lead optimization programs. In the following study, we describe how we have identified small molecules using gene expression profiles derived from one of our internal lead series programs. Furthermore, we show our use of computational tools to optimize these compounds for potency and selectivity. Lastly, we show how compound responsive gene signatures are used to predict xenograft models sensitive to treatment in in vivo efficacy studies. Overall, we will demonstrate how Avalon uses a systems biology approach to provide key information in making decisions in all areas of lead optimization, resulting in both the earlier attrition of compounds with less desirable properties and the selection of promising lead cancer therapeutic candidates. Profiles generated within our beta catenin inhibitor lead optimization program will be used to demonstrate the utility of this approach.