This Small Business Innovative Research (SBIR) Phase I project describes an innovative high throughput protein microarray biochip technology for the use in identifying specific peptides and small compounds (drug candidates) that inhibit BH3-domain-mediated protein-protein interactions. Published studies suggest that, in cancer and autoimmune diseases, programmed cell death (apoptosis) is inhibited by the imbalance of the anti- and pro-apoptotic functions of the bcl-2 family of proteins. These interactions are mediated through the BH3 domain. Modulating these interactions is the goal of the Pharma industry. This proposal describes an innovative, robust, and reliable biochip technology platform that identifies small compounds that specifically inhibit particular BH3-mediated interactions. Multi-domain members of Bcl-2 protein family will be immobilized on modified glass slides to be used as capture molecules for BH3-peptide binding in the presence or absence of an inhibitory peptide or small compound. Cell-based functional assays are incorporated in this approach to validate the physiological relevance of identified inhibitory peptides and compounds. Validated compounds will undergo clinical testing and commercialization. This technology will have broader applications in identifying inhibitors of other disease-relevant protein-protein interactions. POTENTIAL COMMERCIAL APPLICATION: The current challenge facing the pharmaceutical industry is the specificity of inhibitors of protein-protein interaction which are involved in disease onset. Protein microarrays allow the simultaneous interrogation of multiple protein-protein interactions. This offers the advantage of recognizing non-specificity and could translate into improved toxicology profile in the next phase of drug development. Studies proposed here will lead to identification, validation, and commercialization of physiologically-relevant Bcl-2 regulatory small compounds. The platform technology developed here can also be commercialized as a drug discovery platform. Furthermore, the application of this platform technology can easily be expanded to identify inhibitors of other diseases-relevant protein-protein interactions. During Phase II of this SBIR, the technology platform established in Phase I will be scaled up and further validated. Peptides and compounds discovered throughout Phase I and II will be evaluated for their therapeutic potential. Phase II will entail further preclinical studies of the identified compounds in animal models, and commercialization of such compounds as drug candidates.
