SBIR Phase I: Simultaneous In situ Pharmacological Profiling of Gene Regulatory Proteins (GRPs) for Cancer Therapy

这个小企业创新研究（SBIR）第一阶段项目的更广泛的影响/商业潜力是，药物开发人员将首次获得一个平台来测量结合和调节人类基因组的一组蛋白质的全球变化。有了这个工具，制药研究人员将能够针对基因调节蛋白（GRP）调节的癌症、神经系统和其他疾病的药物开发以前无法达到的分子途径。以药物为基础的治疗癌症的有益效果，如多发性骨髓瘤（MM）、小细胞肺癌和神经系统癌症，将改善健康结果：仅在美国，每年约有180万新的癌症病例被诊断出来。如果利用这项技术确定任何靶向grp功能的药物，数百万人将受益。这个小型企业创新研究（SBIR）第一阶段项目将技术从手工工作台应用程序转换为高通量平台。该项目将实施一个基于定量蛋白质组学的药物发现平台，量化小分子对多种细胞和组织类型中GRP蛋白质组的影响。尽管grp与健康和疾病相关，但由于缺乏对小分子口袋的了解和高度的内在蛋白质紊乱，grp在很大程度上被认为是不可药物的，这两者都使生化研究具有挑战性，并且几乎不可能完全表征其结构。该项目将通过实施一种原位研究GRP蛋白质组的方法来消除对GRP生化分离的需要，从而解决这个问题。该方法采用核分离，然后是GRP分离和表征，从而形成一个平台，可以告知药物化合物对染色质结合蛋白质组的影响。该项目将建立第一个数据库，以统计可靠的方式将化合物与它们对基因组结合的蛋白质组的影响联系起来，并与实验室测量（即高分辨率质谱分析）联系起来。整理的数据将包括药物/蛋白质组相互作用的存在以及假和/或阳性的发现率。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is that for the first time, drug developers will have access to a platform to measure global changes to the set of proteins that bind and regulate the human genome. With this tool in hand, pharmaceutical researchers will be able to target molecular pathways previously inaccessible for drug development against Gene Regulatory Protein (GRP)-regulated cancer, neurological, and other conditions. The beneficial effects of drug-based therapies to treat cancers such as multiple myeloma (MM), small cell lung carcinoma, and neurological cancers will improve health outcomes: In the USA alone, about 1.8 million new cancer cases are diagnosed every year. Millions of people will benefit if any drug targeting the function of GRPs is identified using this technology. This Small Business Innovation Research (SBIR) Phase I project converts technology from a manual bench application into a high-throughput platform. This project will implement a quantitative proteomics-based drug discovery platform that quantifies the effects of small-molecules on the GRP proteome in a diversity of cell and tissue types. Despite their relevance in health and disease, GRPs have been largely considered undruggable for several reasons, including the lack of knowledge of small-molecule pockets and high degrees of intrinsic protein disorder, which both make biochemical study challenging and full structural characterization almost impossible. This project will tackle this problem by removing the need for GRP biochemical isolation via implementing a methodology where the GRP proteome is studied in situ. This method employs nuclear fractionation followed by GRP isolation and characterization, resulting in a platform that can inform the effects of drug compounds on the chromatin-bound proteome. This project will build the first database that links in a statistically-robust manner compounds to their effects on the genome-bound proteome, with links to laboratory measurements (i.e., high-resolution mass spectrometry). The curated data will include both presence of drug/proteome interactions and false and/or positive discovery rates.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.