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.

项目总结 14-3-3蛋白处于与癌症相关的不同细胞过程的十字路口，例如信号 转导、细胞周期进程和细胞凋亡。这个中枢蛋白家族通过以下途径调节这些功能 构成14-3-3“相互作用体”的蛋白质-蛋白质相互作用(PPI)的扩展网络。小的 因此，14-3-3相互作用体的分子调控在癌症治疗中具有重要意义，尤其是 鉴于14-3-3蛋白在标准护理药物耐药中的作用。给14-3-3信号集线器下药也 使多个与癌症相关的过程受到干扰。虽然14-3-3 PPI的调制 仍然不发达，天然产物子叶素A提供了一个解决这一问题的分子平台 缺乏症。Cotylenin A作为一种罕见的“分子胶”，稳定了14-3-3/伴侣之间的相互作用。这是 据信是胚胎素A显著的抗癌活性和使癌细胞对现有 治疗的同时保留正常细胞。此外，胚胎素A不同寻常的结合模式具有优势 提高了药物选择性，降低了疗效所需的亲和力。然而，胚轴蛋白A还没有被 由于自然资源的丧失和缺乏有效和易于多样化的合成，开发成一种治疗药物。 这项提案旨在通过化学方法促进以胚轴为基础的癌症疗法的发展。 综合。利用我们集团在有机合成方面的专业知识，我们将开发一条高效和模块化的路线 到胚轴蛋白A。这种接近胚轴蛋白核心的合成策略的概念证明已经 建立，并将促进完成子叶素A的合成。胚轴蛋白核心将使立即 在几个位置多样化，以现有的结晶学数据为基础产生类似物。改型 在早期阶段的综合还将允许在更多地点进行基于结构的多样化，包括一个 这为实现PPI调节的特异性提供了一种新的手段。类似物的抗癌活性 将进行评估，以阐明结构-活性关系。我们还将进行蛋白质组学研究，以确定 受影响的蛋白质靶标。这些知识将指导子叶素的迭代药物化学优化。 研究将在斯克里普斯研究公司进行，这是一家在合成化学和化学方面表现出色的机构 生物学，并促进这两个领域的强大合作。我将接受复杂分子方面的培训 该领域的领军人物瑞安·申维教授的合成，以及通过执行 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。这项工作是 这是对我在研究有机金属反应机理方面的博士培训的补充。