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: 10315983
• 负责人: Christopher John Reinhardt
• 金额: $ 6.6万
• 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/10315983
• 关键词: Stereoisomeric; chemical; probes; targeting; undruggable

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，当时天然产物的分离和表型 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。这种转变 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，在一个示例中， 可靠的、高产率的偶联化学的出现（例如，肽偶联，钯介导的交叉 耦合）和一组简明规则（即，Lipinski的规则）彻底改变了药物化学的效率。 虽然这加快了小分子文库的生产速度和规模，但也不是没有成本的。 现代化学图书馆充斥着扁平的，没有特征的化合物， 每个成员的立构中心和ca. 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，它们对于大分子中涉及的较浅表面（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 已经证明能够结合广泛的挑战性目标，包括那些被认为是 由于它们的骨架和立体化学复杂性，它们是“不可药用的”，因此代表了大多数 FDA批准的药物。多样性导向的合成（DOS），生物学导向的合成，和复杂性， 多样性已经成为有机化学战略，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， 立体化学定义的核。同时，化学蛋白质组学平台，如基于活性的蛋白质 分析，提供了一种全球性的方法来直接绘制小分子和蛋白质之间的相互作用 在原生生物系统中的应用。化学蛋白质组学的努力已经从根本上扩大了 可以被小分子靶向的蛋白质和可配位位点，包括许多以前 缺乏化学探针。该建议旨在整合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架复杂性的小分子文库， 利用这些库发现第一个选择性和细胞活性的化学探针，用于不同的癌蛋白靶点。 在具体目标1中，我们将优化丙烯酰胺配体，这些配体显示出对关键癌症的立体选择性参与。 靶点，包括致癌转录因子和核苷酸交换因子。先进的化合物， 作为直接功能性拮抗剂或双功能降解剂，将用于抑制癌细胞的生长 已经显示出强烈和选择性地依赖于这些癌蛋白。在《目标2》中，我们将扩展 我们的立体异构体库来询问新的三维化学空间。具体而言，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 该文库在与癌细胞死亡的出现形式相关的表型测定中（即，铁性下垂） 寻找新的治疗机制从翻译的角度来看，我们的目标是建立一个 强大而有影响力的工作流程，用于对不可药物治疗的癌症蛋白质组进行药物治疗。