Protein Microarrays in Cancer Drug Discovery

描述(由申请人提供)：项目摘要：这个小型企业创新研究(SBIR)第一阶段项目描述了一种创新的高通量蛋白质微阵列生物芯片技术，用于识别抑制BH3结构域介导的蛋白质-蛋白质相互作用的特定多肽和小化合物(候选药物)。已发表的研究表明，在癌症和自身免疫性疾病中，程序性细胞死亡(细胞凋亡)受到bcl2家族蛋白抗和促凋亡功能失衡的抑制。这些相互作用是通过BH3结构域介导的。调节这些相互作用是制药业的目标。这项提案描述了一个创新、强大和可靠的生物芯片技术平台，它识别出专门抑制特定BH3介导的相互作用的小化合物。将Bc l-2蛋白家族的多结构域成员固定在修饰的玻片上，在存在或不存在抑制性多肽或小分子的情况下，作为BH3多肽结合的捕获分子。基于细胞的功能分析被结合在这种方法中，以验证所识别的抑制性多肽和化合物的生理相关性。经过验证的化合物将进行临床测试和商业化。这项技术将在识别其他与疾病相关的蛋白质-蛋白质相互作用的抑制剂方面有更广泛的应用。 潜在的商业应用：制药业目前面临的挑战是参与疾病发病的蛋白质-蛋白质相互作用抑制剂的特异性。蛋白质微阵列允许同时询问多个蛋白质之间的相互作用。这提供了识别非特异性的优势，并可能在下一阶段的药物开发中转化为改进的毒理学特征。这里提出的研究将导致识别、验证和商业化生理相关的Bcl2调节性小分子化合物。这里开发的平台技术也可以作为药物发现平台进行商业化。此外，该平台技术的应用可以很容易地扩展到识别其他疾病相关蛋白质-蛋白质相互作用的抑制剂。在本次SBIR第二阶段，将对第一阶段建立的技术平台进行规模扩大和进一步验证。在第一阶段和第二阶段中发现的多肽和化合物将被评估其治疗潜力。第二阶段将需要在动物模型中对已确定的化合物进行进一步的临床前研究，并将这些化合物作为候选药物进行商业化。

DESCRIPTION (provided by applicant): PROJECT SUMMARY: 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.