A collaborative structural hub to promote Cancer Center science and drug design

促进癌症中心科学和药物设计的协作结构中心

• 批准号: 9221629
• 负责人: Alexander Aleshin
• 金额: $ 14.56万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221629
• 关键词: Affinity; Allosteric Site; Award; Basic Science; Binding; CNKSR1 gene; Cancer Center; Collaborations; Complex; Crystallization; Development; Drug Design; Environment; Funding; Goals; Lead; Ligand Binding; Ligand Binding Domain; Link; Malignant Neoplasms; Methodology; Movement; PH Domain; Pathway interactions; Phosphotransferases; Postdoctoral Fellow; Principal Investigator; Property; Proteins; Research; Research Personnel; Resolution; Science; Scientist; Site; Solubility; Specificity; Structure; Students; Substrate Specificity; Training; Work; base; bench to bedside; biophysical analysis; cost efficient; drug candidate; drug discovery; experience; inhibitor/antagonist; novel; novel therapeutics; research clinical testing; screening; skills; success; synchrotron radiation

ABSTRACT The goal of this project is to provide a collaborative structural "hub" to promote SBPMDI Cancer Center science, drug discovery, structure-based drug design and inhibitory mechanism. To understand the mechanism of a discovered probe/lead compound and/or to enhance its potency, a co-crystal structure of the probe with a target protein is required. This type of work typically requires troubleshooting and optimization, because compounds obtained by screening often bind with unknown affinity, have solubility issues which complicate co-crystallization and/or bind at unknown allosteric sites. I have already succeeded on six project fronts in collaboration with Principal Investigators at the SBPMDI Cancer Center. Four of these projects have NCI funding (RXRα ligand binding domain, Hif2α PASB domain, PLEKHA7 PH domain, FAS TE domain) and two are part of NCI applications currently under review (TAO3 kinase domain and ALDOA). The RXRα work revealed distinct inhibitory mechanisms between very similar lead compounds. The Hif2α PASB work demonstrated the structural basis of tight inhbition. The PLEKHA7 PH and TAO3 kinase domains are novel crystal structures with bound ligand; in the first case, revealing a structural basis for substrate specificity and in the second case, pointing to a pathway to enhance inhibitor specificity. The ALDOA project has revealed the structural basis of novel allosteric covalent inhibitors, as well as potential S-nitrosylation sites that may determine subcellular localization. All six targets are novel (PLEKHA7, TAO3 and ALDOA), or established (RXRα, Hif2α and FAS TE) cancer targets, and I plan to continue collaborations on their further development from hit-to-lead. I have also added to the list the PH domain of CNK1, a KRas-linked cancer target with unique properties. Based on my varied experiences, I have developed a cost efficient methodology with a high likelihood of success, employing biophysical analysis, NMR, high-throughput crystallization and fine-focus synchrotron radiation. I also encourage and provide training to postdocs, students, staff scientists and technicians, who wish to participate in structural studies. The NCI R50 award will allow me a firm financial basis on which to extend current studies and initiate new collaborations to include investigators with newly discovered targets or probes but who currently lack the funding to support my collaborative work. Understanding structural and mechanistic aspects of new drug candidates is required to move hit compounds toward leads and a clinical testing funnel, and aid Principal Investigators in obtaining funding for their research, thereby expediting the movement of basic science discoveries from "bench to bedside".

抽象的 该项目的目标是提供一个协作结构“中心”来促进 SBPMDI 癌症中心的发展 科学、药物发现、基于结构的药物设计和抑制机制。要了解 已发现的探针/先导化合物的机制和/或增强其效力，共晶结构 需要带有目标蛋白的探针。此类工作通常需要故障排除和优化， 因为通过筛选获得的化合物通常以未知的亲和力结合，存在溶解度问题， 使共结晶复杂化和/或在未知的变构位点结合。我已经成功完成了六个项目 与 SBPMDI 癌症中心的主要研究人员合作。其中四个项目已 NCI 资助（RXRα 配体结合域、Hif2α PASB 域、PLEKHA7 PH 域、FAS TE 域）和 其中两个是目前正在审查的 NCI 申请的一部分（TAO3 激酶结构域和 ALDOA）。 RXRα 工作原理 揭示了非常相似的先导化合物之间不同的抑制机制。 Hif2α PASB 工作 证明了严格抑制的结构基础。 PLEKHA7 PH 和 TAO3 激酶结构域是新颖的 具有结合配体的晶体结构；在第一种情况下，揭示了底物特异性的结构基础 第二种情况，指出了增强抑制剂特异性的途径。 ALDOA 项目揭示了 新型变构共价抑制剂的结构基础，以及可能的潜在 S-亚硝基化位点 确定亚细胞定位。所有六个目标都是新颖的（PLEKHA7、TAO3 和 ALDOA）或已确定的 （RXRα、Hif2α 和 FAS TE）癌症靶点，我计划继续合作进一步开发它们 从命中到领先。我还将 CNK1 的 PH 结构域添加到列表中，这是一个与 KRas 相关的癌症靶点，具有独特的 特性。根据我的不同经验，我开发了一种具有高成本效益的方法 成功的可能性，采用生物物理分析、核磁共振、高通量结晶和精细聚焦 同步加速器辐射。我还鼓励并为博士后、学生、科学家和人员提供培训 希望参与结构研究的技术人员。 NCI R50 奖项将使我拥有坚定的财务实力 在此基础上扩展当前的研究并启动新的合作，以纳入新的研究人员 发现了目标或探测器，但目前缺乏资金来支持我的协作工作。 需要了解新候选药物的结构和机制方面才能转移热门化合物 寻找线索和临床测试漏斗，并帮助主要研究人员为其研究获得资金， 从而加速基础科学发现从“实验室到临床”的转变。