A Cell-Based Assay to Find Inhibitors of Chronic Active B-Cell Receptor Signaling

描述(申请人提供)：某些弥漫性大B细胞淋巴瘤(DLBCL)的活化B细胞(ABC)亚型对标准治疗反应不佳，最近由候选人和以前的同事发现依赖B细胞受体(BCR)激活典型的NF：B途径和其他对其生存至关重要的途径。该应用程序的主要目标是与分子文库探针生产中心网络(MLPCN)合作，使用MLPCN已经建立的基于细胞的初步分析方法，寻找这一过程的小分子抑制剂，称为“慢性活性BCR信号传递”(CABS)。该分析将在CABS依赖的线上进行，并将与反筛选和二次分析相结合，用于识别CABS的抑制剂，这些抑制剂可以优化为其鲜为人知的机制的化学探针，并作为针对ABC-DLBCL的靶向治疗的候选药物开发。这项拟议的项目将是申请人先前关于如何在ABC-DLBCL中结构性地激活核因子：B通路的研究的继续，以确定潜在的提高特异性的治疗靶点。找到驾驶室的化学探测器将促进申请者的直接职业目标，即进一步发现这一途径，并成为一名独立的调查人员。找到真正的药物开发候选者将推动申请者将其研究成果扩展到临床领域的长期目标，这与他最近加入的一个在新疗法的开发和临床测试方面表现出色的部门是一致的。 公共卫生相关性：许多不同类型的癌症依赖于特定和异常激活的生物途径，这些途径的抑制剂有可能提供高效的靶向治疗，同时减少副作用。当在癌细胞系中发现关键途径时，可以对该途径进行工程改造，以方便地报告该途径的活动水平，从而用于筛选该途径抑制剂的大型化合物库。该项目将使用这一方法来寻找在一种对标准治疗反应较差的B细胞癌(淋巴瘤)中激活的关键途径的抑制物，帮助研究这一途径，并可能提供作为靶向治疗的候选药物。

DESCRIPTION (provided by applicant): Certain cell lines of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which responds poorly to standard therapy, have recently been discovered by the candidate and former colleagues to rely on the B-cell receptor (BCR) for activation of the canonical NF:B pathway and other pathways essential for their survival. The principal goal of the application is to collaborate with the Molecular Libraries Probe Production Centers Network (MLPCN), using a cell-based primary assay already established by the MLPCN, to find small-molecule inhibitors of this process termed "chronic active BCR signaling" (CABS). The assay will be performed in a CABS-dependent line, and in combination with counterscreens and secondary assays, will be used to identify inhibitors of CABS that can be optimized to serve as chemical probes of its poorly- understood mechanisms, and candidates for drug development as targeted therapy against ABC-DLBCL. The proposed project would be a continuation of the applicant's previous investigations into how the NF:B pathway is constitutively activated in ABC-DLBCL, identifying potential therapeutic targets of increasing specificity. Finding chemical probes of CABS would advance the applicant's immediate career goals of making further discoveries about this pathway, and becoming established as an independent investigator. Finding serious candidates for drug development would advance the applicant's long-term goals of extending his research findings into the clinical arena, in keeping with his having recently joined a department which excels in the development and clinical testing of new therapies. PUBLIC HEALTH RELEVANCE: Many different types of cancer depend on specific and abnormally-activated biological pathways, and inhibitors of these pathways have the potential to provide highly effective targeted therapies with reduced side effects. When a critical pathway is found in a cancer cell line, the line can be engineered to conveniently "report" on that pathway's activity level, and thus be used to screen large libraries of chemical compounds for inhibitors of the pathway. This project will use this approach to find inhibitors of a critical pathway activated in one type of cancer of B cells (lymphomas) that responds poorly to standard therapy, helping in studies of this pathway and possibly providing candidates for development as targeted therapy.