Assay development and screening for molecular targets and discovery

检测开发工作的重点是高通量检测的配置、优化和验证，以筛选纯化合物文库和天然产物提取物，用于特定分子和细胞靶点以及相关细胞表型的调节剂。该部门还开发和应用分析方法来表征作用机制研究中的活性分子，并优先考虑化合物，以进一步发展作为探针和治疗剂的应用。开发了9项基于细胞的测定（除了与蛋白质化学和分子生物学部门合作开发的4项生化测定外），进行了11项高通量筛选（HTS）活动，并进行了12项测定以支持天然产物化学。对来自已完成HTS活动的大量命中进行生物表征研究，包括利用化学基因组学平台评估转录调节和细胞毒性的天然产物调节剂的作用机制。以天然产物为重点的HTS也导致了先导化合物的开发，这些先导化合物在药物摄取、免疫调节、转录调节的临床前模型以及光神霉素类似物的临床前开发中得到了进一步评估。

Assay development efforts focus on the configuration, optimization and validation of high-throughput assays to screen pure compound libraries and natural product extracts for modulators of specific molecular and cellular targets and associated cellular phenotypes. The section also develops and applies assays to characterize active molecules in mechanism of action studies and to prioritize compounds for further advancement toward utilization as probes and therapeutics. Nine cell-based assays were developed (in addition to 4 biochemical assays developed in collaboration with the Protein Chemistry and Molecular Biology Section), 11 high-throughput screening (HTS) campaigns were performed and 12 assays were performed in support of natural products chemistry. Biological characterization studies were performed on numerous hits from completed HTS campaigns, including utilization of a chemical genomics platform to assess mechanisms of action of natural product modulators of transcriptional regulation and cytotoxicity. Natural products-focused HTS has also led to development of lead compounds being further assessed in pre-clinical models of drug uptake, immunoregulation, transcriptional regulation, as well as preclinical development of a mithramycin analog.