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.

项目摘要 药物化学在20世纪80年代发生了范式转变，当时天然产物分离和表型 筛选在很大程度上被组合化学和基于结构的药物设计所取代。这一转变 是由分子生物学、结构生物学和合成化学的关键进展推动的。例如, 可靠、高产的偶联化学的出现(例如，多肽偶联、钯介导的交叉 耦合)和一套简明的规则(即利平斯基规则)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，但也不是没有代价的。 现代化学图书馆里满是扁平的、没有特征的化合物，其中包含的化合物不到一种 每个成员的立体中心和大约20%的SP3含量。这些特性有利于进行深度绑定 蛋白质中的口袋；然而，它们不适合参与大分子(例如， 蛋白质-蛋白质、蛋白质-寡核苷酸)相互作用。另一方面，天然产品及其衍生品 已被证明有能力约束一系列具有挑战性的目标，包括那些被认为 由于其骨骼和立体化学的复杂性而无法下药“，因此代表了大多数 FDA批准的药物。面向多样性的合成(DOS)、面向生物的合成和从复杂性到复杂性的合成 多样性已经作为有机化学策略出现，它们拥抱了天然产品复杂性的力量 建立不同的化学库，强调密集的官能化、熵限制和 立体化学定义的核心。同时，化学蛋白质组平台，如基于活性的蛋白质 正在提供一种全球方法来直接绘制小分子和蛋白质之间的相互作用图 第一次在本地生物系统中发现了。化学蛋白质组学的努力从根本上扩大了 可被小分子靶向的蛋白质和可配基部位，包括以前的许多例子 缺乏化学探头。这项建议旨在整合DOS、共价化学和化学的原理 蛋白质组学创建具有立体化学和骨架复杂性的高度创新的小分子文库，并 使用这些文库来发现第一个针对不同癌蛋白靶点的选择性和细胞活性的化学探针。 在具体目标1中，我们将优化丙烯酰胺配体，以显示与关键癌症的立体选择性结合 靶点，包括致癌转录因子和核苷酸交换因子。高级化合物，或者 作为直接功能拮抗剂或双功能降解剂，将被用于抑制癌细胞的生长 已被证明强烈和选择性地依赖于这些癌蛋白。在具体目标2中，我们将扩大 我们的立体异构体文库来询问新的三维化学空间。具体地说，我们将建立一个 亲电四氢喹啉立体异构体化合物文库(50个衍生物，200个异构体)和筛选 该文库在表型分析中与新出现的癌细胞死亡形式(即铁下垂)相关，并有一个焦点 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 强大而有效的工作流程，用于给无法用药的癌症蛋白质组下药。