Gold-based pharmacophore synthetic strategies as a basis for transcription factor modulator discovery

基于金的药效基团合成策略作为转录因子调节剂发现的基础

• 批准号: 10112947
• 负责人: Samuel Gorman Awuah
• 金额: $ 27.17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112947
• 关键词: 3-Dimensional; Affinity; Amino Acids; Animals; Area; Auranofin; Binding; Binding Sites; Biochemical; Biological Process; Cancer Biology; Cells; Centers of Research Excellence; Chemicals; Chemistry; Complex; Computer Models; Cysteine; DNA Binding; Data; Development; Disease; E-Box Elements; Electronics; Evaluation; Exhibits; FDA approved; Gene Expression Regulation; Genetic Transcription; Glutathione; Goals; Gold; Heterodimerization; Histidine; Individual; Laboratories; Lead; Libraries; Ligands; Lysine; Malignant Neoplasms; Medical; Membrane Proteins; Mentorship; Methods; Modeling; Modification; Molecular; Molecular Medicine; Natural Products; Nature; Nitrogen; Nucleic Acids; Oncogenic; Organic Synthesis; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Post-Translational Protein Processing; Process; Property; Proteins; Reaction; Regulation; Research; Research Support; Rheumatoid Arthritis; Safety; Science; Selenocysteine; Side; Site; Structural Models; Structure; Structure-Activity Relationship; Surface; System; Testing; Transition Elements; Validation; assay development; base; c-myc Genes; catalyst; cellular targeting; cytotoxicity; design; functional group; improved; inhibitor/antagonist; innovation; interest; metal complex; novel; pharmacophore; programs; protein phosphatase inhibitor-2; protein protein interaction; scale up; screening; small molecule; success; therapeutic target; time use; transcription factor

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Transcription factor (TF) deregulation underlies numerous diseases including cancer; however, the selective targeting of TFs with small molecule probes/leads remains elusive. Our research program seeks to exploit the unique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for TF probe/lead modulator discovery. Specifically, we seek to develop novel and efficient reaction methods to rapidly construct diverse Au-based pharmacophore libraries and to leverage these unique compound sets, and a streamlined screening strategy, to discover selective modulators of the model oncogenic transcription factor c- MYC. This study will develop a generalizable platform to target ‘undruggable’ targets such as protein-protein interfaces or TFs, using ‘caged’ gold centers via two ways: i) directly ligate gold to specific amino acids, or ii) covalently modify specific amino acids by transfer of coordinated ligands via reductive elimination in a manner similar to chemistry performed by transition metal-based catalysts. The studies will extend the breadth of stable gold ligands through optimization of Au catalytic processes, advance our understanding of the tunable reactivity and bioorthogonality of Au-based pharmacophores and potentially set the stage for a generalized strategy to target ‘undruggable’ proteins. A primary innovation of the proposed studies is the potential to dramatically alter, via covalent modification, protein surface structure/electronics and thereby influence function. CPRI mentorship and research support cores will further facilitate this project in a number of key ways. Specifically, the Computational Core will assist in the development of new predictive structure-activity relationship (SAR) models for Au-based probes and computational c-MYC/MAX-ligand structural models to guide probe design; the Translational Core will facilitate assay development, validation, and implementation (and eventually first in animal assessments including PK and ADMET); and the COBRE for Molecular Medicine’s Organic Synthesis Core will strategically support ligand synthesis/scale-up. This will also be augmented by a COBRE mentorship team with extensive expertise in transcription factor lead discovery, cancer biology, and pharmaceutical science.

项目摘要/摘要--项目1 转录因子(TF)的解除调控是包括癌症在内的许多疾病的基础；然而，选择性的 以小分子探针/引线为靶点的TF仍然难以捉摸。我们的研究计划试图利用 金基[Au(I)和Au(III)]配合物作为转铁蛋白基础的独特空间性质和化学反应活性 探测/引导调制器发现。具体地说，我们寻求开发新的和有效的反应方法来快速 构建不同的基于Au的药效团文库，并利用这些独特的化合物集，以及 简化筛选策略，以发现模型致癌转录因子c-2的选择性调节子。 MYC。这项研究将开发一个可推广的平台，以靶向诸如蛋白质-蛋白质等不能下药的靶标 界面或TF，通过两种方式使用“笼中”的黄金中心：i)直接将金与特定的氨基酸连接，或ii) 通过还原消除转移配位配体来共价修饰特定的氨基酸 类似于以过渡金属为基础的催化剂执行的化学。这些研究将扩大稳定的广度 通过优化Au的催化过程，提高我们对可调反应性的理解 和基于Au的药效团的生物正交性，并有可能为推广战略奠定基础 以“无法下药”的蛋白质为目标。拟议研究的一个主要创新是有可能显著改变， 通过共价修饰，蛋白质表面结构/电子结构发生改变，从而影响功能。 CPRI的指导和研究支持核心将在几个关键方面进一步促进这一项目。 具体地说，计算核心将协助开发新的预测结构--活动 金基探针的关系(SAR)模型和用于指导的计算c-MYC/MAX-配体结构模型 探针设计；翻译核心将促进分析开发、验证和实施(和 最终在包括PK和ADMET在内的动物评估中排名第一)；以及分子医学科布雷 有机合成核心将在战略上支持配体合成/放大。这一点还将通过一个 Cobre导师团队在转录因子先导发现、癌症生物学和 药学。