Mays Cancer Center at UT Health SA

项目摘要-药物发现和结构生物学共享资源 药物发现和结构生物学共享资源(DDSB)是一个新的梅斯癌症中心(MCC)- 支持综合服务的共享资源，更好地满足MCC用户的需求。 DDSB的目的是为MCC调查人员提供最先进的能力，用于癌症研究- 原子和分子水平上的相关大分子，它们如何与其他大分子相互作用 作为配体，并用于识别可使用先进工具(如X射线)靶向的小分子 结晶学、核磁共振和表面等离子体共振(SPR)以及高通量筛选 (HTS)技术-包括但不限于基于细胞的表型高含量成像和纯化 基于组件的HTS。DDSB为MCC结束癌症的总体使命做出了关键贡献 通过提供一个整合了结构生物学、分子表型和药物的综合平台 发现扩展癌症病因的知识，发现癌症相关靶点，并确定潜在的 治疗学。DDSB由四个集成模块组成：(A)小分子探针和药物发现， (B)核磁共振，(C)X射线结晶学，和(D)大分子相互作用。每个模块都由一位专家领导 由Matthew Hart博士提供的所有模块的监督。根据项目的不同，DDSB可以 执行涉及一个或多个模块的重点研究，或执行涉及所有模块的综合性研究。 在上一次报告所述期间(2014-2018年)，DDSB与40名MCC成员合作，他们使用了总数的53% 服务时间到了。在此期间，DDSB资助了20种与癌症有关的出版物。还生成了DDSB活动 10个先导化合物在结构指导优化阶段的管道和18个早期项目，~50% 其中，预计将在两年内实现领先优化。在下一个资助期结束时，我们 预计已经向癌症研究人员提供了5-8条新的经过审查的线索，准备进入临床前阶段。至 为了实现其目标，DDSB将建立先进的新型X射线结晶学工具，高通量 筛查(包括以迄今“不能下药的”靶点为目标的方法)，以及定向癌症相关靶点 退化。在下一个资助期内，我们期待着DDSB继续推动我们对 推动癌症的机制，并确定新的癌症治疗方法，以供未来临床测试。这个 DDSB统一了多个具有挑战性的能力，个人调查人员因成本、所需成本而难以追求 仪器的维护，以及使用这些技术所需的专业知识。因此，DDSB 对于MCC实现其战略目标--翻译对过程的分子理解--至关重要 这为癌症提供了新的治疗方法。

Project Summary—Drug Discovery and Structural Biology Shared Resource The Drug Discovery and Structural Biology Shared Resource (DDSB) is a new Mays Cancer Center (MCC)- supported Shared Resource that combines comprehensive services to better meet the needs of MCC users. The purpose of the DDSB is to provide state-of-the-art capabilities to MCC investigators for the study of cancer- related macromolecules at the atomic and molecular levels, how they interact with other macromolecules such as ligands, and for identification of small molecules that can target them using advanced tools such as X-ray crystallography, nuclear magnetic (NMR) and surface plasmon resonance (SPR), and high-throughput screening (HTS) technologies – including, but not limited to, cell-based phenotypic high-content imaging-based and purified component-based HTS. The DDSB makes critical contributions to the MCC’s overarching mission to end cancer by providing a comprehensive platform that integrates structural biology, molecular phenotypes, and drug discovery to expand knowledge on the etiology of cancer, discover cancer-relevant targets, and identify potential therapeutics. The DDSB is composed of four integrated modules: (a) Small Molecule Probe and Drug Discovery, (b) NMR, (c) X-ray Crystallography, and (d) Macromolecular Interactions. Each module is led by an expert in that field, with oversight of all modules provided by Matthew Hart, Ph.D. Depending on the project, DDSB can perform focused studies involving one or more modules, or perform integrative studies involving all modules. During the last reporting period (2014-2018), the DDSB worked with 40 MCC members who used 53% of total service time. In this period, the DDSB supported 20 cancer-related publications. DDSB activities also generated a pipeline of 10 lead compounds in the structure-guided optimization stage and 18 early-stage projects, ~50% of which are expected to reach lead optimization within two years. At the end of the next funding period we expect to have delivered 5-8 new vetted leads, ready to move into preclinical stages, to cancer investigators. To further its goals, the DDSB will establish advanced novel tools for X-ray crystallography, high-throughput screening (including approaches that target heretofore “undruggable” targets), and directed cancer-related target degradation. During the next funding period, we expect the DDSB to continue advancing our understanding of mechanisms that drive cancers and identifying novel cancer therapeutics to be tested for future clinical use. The DDSB unites multiple capabilities challenging for individual investigators to pursue because of the cost, required maintenance of the instrumentation, and breadth of expertise needed to use these technologies. Thus, the DDSB is essential for the MCC to achieve its strategic goal of translating a molecular understanding of the processes that underlie cancer into novel therapies.