Small molecule modulation of 14-3-3 protein-protein interactions

14-3-3 蛋白质-蛋白质相互作用的小分子调节

• 批准号: 10607941
• 负责人: Stephen I Ting
• 金额: $ 6.87万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607941
• 关键词: Address; Advanced Development; Affect; Affinity; Alder plant; Antineoplastic Agents; Apoptosis; Binding; Biological; Biology; Cancer Control; Cancer cell line; Cell Cycle Progression; Cell physiology; Chemicals; Collaborations; Complex; Crystallography; Data; Development; Drug resistance; Family; Fostering; Glues; Goals; Institution; Investigation; Knowledge; Malignant Neoplasms; Modification; Molecular; Natural Products; Natural Source; Normal Cell; Oncogenic; Organic Synthesis; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Process; Proteins; Proteomics; Reaction; Research; Resistance; Role; Route; Signal Transduction; Site; Specificity; Structure; Structure-Activity Relationship; Synthesis Chemistry; Therapeutic; Training; Work; analog; anti-cancer; anticancer activity; cancer cell; cancer therapy; chemical synthesis; design; improved; insight; interest; novel; prevent; protein protein interaction; small molecule; standard of care; therapeutic candidate; therapeutic development; tumorigenic

PROJECT SUMMARY 14-3-3 proteins are at the crossroads of diverse cellular processes relevant to cancer, such as signal transduction, cell cycle progression and apoptosis. This family of hub proteins regulates these functions through an expansive network of protein-protein interactions (PPIs) that constitute the 14-3-3 “interactome.” Small molecule modulation of the 14-3-3 interactome is therefore of significant interest for cancer treatment, especially given the role of 14-3-3 proteins in resistance to standard of care drugs. Drugging the 14-3-3 signaling hub also enables multiple cancer-relevant processes to be perturbed in concert. Although modulation of 14-3-3 PPIs remains underdeveloped, the natural product cotylenin A presents a molecular platform to address this deficiency. Cotylenin A stabilizes 14-3-3/partner interactions by functioning as a rare “molecular glue.” This is believed to underlie cotylenin A’s notable anticancer activity and ability to sensitize cancer cells to existing treatments while sparing normal cells. Additionally, cotylenin A’s uncommon binding mode carries advantages of improved drug selectivity and lower affinities required for efficacy. However, cotylenin A has not been developed as a therapeutic due to loss of natural sources and lack of efficient and readily diversifiable syntheses. This proposal seeks to invigorate the development of cotylenin-based cancer therapies through chemical synthesis. Leveraging our group’s expertise in organic synthesis, we will develop an efficient and modular route to cotylenin A. Proof of concept for this synthetic strategy to access the cotylenin core has already been established, and will facilitate completion of the cotylenin A synthesis. The cotylenin core will enable immediate diversification at several positions to generate analogues based on existing crystallographic data. Modification of the synthesis at early stages will also allow structure-based diversification at additional sites, including one that provides a novel means to achieve specificity in PPI modulation. The anticancer activity of the analogues will be evaluated to elucidate structure-activity relationships. We will also conduct proteomic studies to identify the affected protein targets. This knowledge will guide iterative medicinal chemistry optimization of cotylenins. Research will be carried out at Scripps Research, an institution that excels in synthetic chemistry and chemical biology, and fosters strong collaboration across the two fields. I will receive training in complex molecule synthesis from Prof. Ryan Shenvi, a leader in the field, as well as training in chemical biology by performing biological and proteomic studies in collaboration with Prof. Chris Parker at Scripps Research. This work is complimentary to my doctoral training in the study of organometallic reaction mechanisms.

项目概要 14-3-3 蛋白处于与癌症相关的多种细胞过程的十字路口，例如信号 该中心蛋白家族通过转导、细胞周期进程和细胞凋亡来调节这些功能。 构成 14-3-3“小相互作用组”的广泛的蛋白质-蛋白质相互作用 (PPI) 网络。 因此，14-3-3 相互作用组的分子调节对于癌症治疗具有重要意义，尤其是 考虑到 14-3-3 蛋白在对标准护理药物产生耐药性中的作用，还对 14-3-3 信号中枢进行药物治疗。 尽管 14-3-3 PPI 的调节能够使多个癌症相关过程同时受到干扰。 仍然不发达，天然产物 cotylenin A 提供了一个分子平台来解决这个问题 子叶蛋白 A 通过充当一种罕见的“分子胶”来稳定 14-3-3/伴侣的相互作用。 据信是子叶蛋白 A 显着的抗癌活性和使癌细胞对现有的敏感性的能力的基础 此外，cotylenin A 不常见的结合模式具有优势。 然而，Cotylenin A 尚未得到改善的药物选择性和较低的药效所需的亲和力。 由于天然来源的丧失和缺乏有效且易于多样化的合成方法而被开发为一种治疗方法。 该提案旨在通过化学方法促进基于子叶素的癌症疗法的发展 利用我们团队在有机合成方面的专业知识，我们将开发一条高效的模块化路线。 子叶蛋白 A。这种获取子叶蛋白核心的合成策略的概念证明已经得到证实 建立，并将促进完成子叶素 A 合成，子叶素核心将能够立即实现。 根据现有晶体学数据在多个位置进行多样化以生成类似物。 早期阶段的合成也将允许在其他地点进行基于结构的多样化，包括一个 这提供了一种新的方法来实现 PPI 类似物的抗癌活性特异性调节。 我们还将进行评估以阐明结构-活性关系。 这些知识将指导子叶蛋白的迭代药物化学优化。 研究将在斯克里普斯研究中心进行，该机构在合成化学和化学方面表现出色 生物学，并促进两个领域的强有力合作我将接受复杂分子的培训。 该领域的领导者 Ryan Shenvi 教授的合成，以及通过执行化学生物学培训 与斯克里普斯研究中心的克里斯帕克教授合作进行生物学和蛋白质组学研究。 对我在有机金属反应机制研究方面的博士训练的赞扬。