Stereoisomeric chemical probes for targeting undruggable oncoproteins

用于靶向不可成药癌蛋白的立体异构化学探针

• 批准号: 10676197
• 负责人: Christopher John Reinhardt
• 金额: $ 7.18万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676197
• 关键词: 3-Dimensional; Acrylamides; Address; Anti-Bacterial Agents; Antineoplastic Agents; Antiparasitic Agents; Benchmarking; Binding; Biological Assay; Biology; Cancer Cell Growth; Cancer cell line; Cell Death; Cells; Characteristics; Chemicals; Chemistry; Collaborations; Coupled; Coupling; DNA-Protein Interaction; Dependence; Drug Design; Drug Targeting; Environment; Essential Drugs; FDA approved; Generations; Guanine Nucleotide Exchange Factors; Human; IKBKB; Isomerism; Left; Libraries; Ligands; Malignant Neoplasms; Maps; Mediating; Methodology; Methods; Modernization; Molecular Biology; Molecular Structure; Morphologic artifacts; Natural Products; Nucleotides; Oligonucleotides; Oncogenic; Oncoproteins; Organic Chemistry; Palladium; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Production; Property; Proteins; Proteome; Proteomics; Site; Stereoisomer; Structure; Surface; Surveys; Synthesis Chemistry; Tertiary Protein Structure; Therapeutic; Time; Viral; Work; activity-based protein profiling; antagonist; anti-cancer; anticancer activity; biological systems; cancer cell; cancer type; combinatorial chemistry; cost; density; drug discovery; innovation; member; mimicry; natural product derivative; natural product inspired; new therapeutic target; next generation; novel; novel therapeutics; pharmacophore; protein function; protein purification; scaffold; screening; skeletal; small molecule; small molecule libraries; structural biology; success; transcription factor; ubiquitin-protein ligase

Project Summary Medicinal chemistry saw a paradigm shift in the 1980’s when natural product isolation and phenotypic screens were largely replaced by combinatorial chemistry and structure-based drug design. This transformation was prompted by key advances in molecular biology, structural biology, and synthetic chemistry. For example, the advent of reliable, high yielding coupling chemistries (e.g., peptide coupling, palladium-mediated cross couplings) and a set of concise rules (i.e., Lipinski’s rules) revolutionized the efficiency of medicinal chemistry. Although this expedited the rate of production and size of small-molecule libraries, it was not without a cost. Modern chemical libraries are overpopulated with flat, nondescript compounds that contain fewer than one stereocenter per member and ca. 20% sp3 content. These properties are favorable for engaging deep binding pockets in proteins; however, they are ill-equipped for the shallower surfaces involved in macromolecular (e.g., protein-protein, protein-oligonucleotide) interactions. On the other hand, natural products and their derivatives have proven capable of binding a wide range of challenging targets, including those that are considered “undruggable” due to their skeletal and stereochemical complexity”, and consequently represent the majority of FDA-approved drugs. Diversity-oriented synthesis (DOS), biology-oriented synthesis, and complexity-to- diversity have emerged as organic chemistry strategies that embrace the power of natural product complexity to establish diverse chemical libraries emphasizing densely functionalized, entropically constrained, and stereochemically defined cores. Concurrently, chemical proteomic platforms, such as activity-based protein profiling, are providing a global approach to map the interactions between small molecules and proteins directly in native biological systems for the first time. Chemical proteomic efforts have radically expanded the number of proteins and ligandable sites that can be targeted by small molecules, including many examples that previously lacked chemical probes. This proposal aims to integrate the principles of DOS, covalent chemistry, and chemical proteomics to create highly innovative small-molecule libraries of stereochemical and skeletal complexity and to use these libraries to discover the first selective and cell-active chemical probes for diverse oncoprotein targets. In Specific Aim 1, we will optimize acrylamide ligands that show stereoselective engagement of key cancer targets, including oncogenic transcription factors and nucleotide exchange factors. Advanced compounds, either as direct functional antagonists or bifunctional degraders, will be used to suppress the growth of cancer cells that have been shown to strongly and selectively depend on these oncoproteins. In Specific Aim 2, we will expand our stereoisomeric library to interrogate new three-dimensional chemical space. Specifically, we will establish a library of electrophilic, tetrahydroquinoline stereoisomeric compounds (50 derivatives, 200 isomers) and screen this library in phenotypic assays relevant to emerging forms of cancer cell death (i.e., ferroptosis) with a focus on identifying new therapeutic mechanisms of action. From a translational perspective, we aim to establish a robust and impactful workflow for drugging the undruggable cancer proteome.

项目概要 药物化学在 20 世纪 80 年代发生了范式转变，当时天然产物的分离和表型研究 筛选很大程度上被组合化学和基于结构的药物设计所取代。这种转变 是由分子生物学、结构生物学和合成化学的重大进展推动的。例如， 可靠、高产的偶联化学的出现（例如肽偶联、钯介导的交叉反应） 耦合）和一套简洁的规则（即利宾斯基规则）彻底改变了药物化学的效率。 尽管这加快了小分子文库的生产速度和规模，但这并非没有成本。 现代化学库中充斥着扁平、无特色的化合物，其中含有的化合物少于一种 每个成员的立体中心和大约。 20% sp3 含量。这些特性有利于深度结合 蛋白质中的口袋；然而，它们对于涉及大分子的较浅表面（例如， 蛋白质-蛋白质、蛋白质-寡核苷酸）相互作用。另一方面，天然产物及其衍生物 已被证明能够结合广泛的具有挑战性的目标，包括那些被认为 由于其骨架和立体化学的复杂性，“不可成药”，因此代表了大多数 FDA批准的药物。面向多样性的合成（DOS）、面向生物学的合成和复杂性到- 多样性已成为有机化学策略，它拥抱天然产物复杂性的力量 建立多样化的化学库，强调密集功能化、熵约束和 立体化学定义的核心。同时，化学蛋白质组平台，例如基于活性的蛋白质 分析，提供了一种直接绘制小分子和蛋白质之间相互作用的全局方法 首次在本地生物系统中。化学蛋白质组学的努力从根本上扩大了蛋白质组学的数量 可以被小分子靶向的蛋白质和可配位位点，包括以前的许多例子 缺乏化学探针。该提案旨在整合 DOS、共价化学和化学的原理 蛋白质组学创建高度创新的立体化学和骨骼复杂性小分子库，并 使用这些库来发现针对不同癌蛋白靶点的第一个选择性和细胞活性化学探针。 在具体目标 1 中，我们将优化显示关键癌症立体选择性参与的丙烯酰胺配体 靶标，包括致癌转录因子和核苷酸交换因子。先进的化合物，要么 作为直接功能拮抗剂或双功能降解剂，将用于抑制癌细胞的生长 已被证明强烈且选择性地依赖于这些癌蛋白。在具体目标 2 中，我们将扩展 我们的立体异构库来探究新的三维化学空间。具体来说，我们将建立一个 亲电四氢喹啉立体异构化合物库（50 种衍生物，200 种异构体）和筛选 该库用于与新兴形式的癌细胞死亡（即铁死亡）相关的表型测定，重点是 确定新的治疗作用机制。从翻译的角度来看，我们的目标是建立一个 用于对不可成药的癌症蛋白质组进行药物治疗的强大而有效的工作流程。