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; 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.

项目摘要 14-3-3蛋白处于与癌症相关的潜水细胞过程的十字路口，例如信号 转导，细胞周期进程和凋亡。这个集线器蛋白家族通过 构成14-3-3“ Interactome”的蛋白质蛋白质相互作用（PPI）的额外网络。小的 因此 鉴于14-3-3蛋白在对护理药物标准药物的抗性中的作用。吸毒14-3-3信号轮毂也 使多个与癌症相关的过程能够在协同中受到干扰。尽管调制为14-3-3 ppis 仍然不发达，天然产物小球蛋白A为解决这个问题提供了一个分子平台 不足。小球蛋白A通过用作罕见的“分子胶”来稳定14-3-3/伴侣的相互作用。这是 人们认为是小甲基烯肽A的著名抗癌活性和对现有癌细胞感知癌细胞的能力的基础 在保留正常细胞的同时处理。此外，小球素A的不常见绑定模式具有优势 提高药物选择性和效率所需的较低亲和力。但是，小球蛋白A尚未 由于自然来源的丧失以及缺乏有效且易于多样化的合成而开发为治疗性。 该提案旨在通过化学来激发基于小甲基烯的癌症疗法的发展 合成。利用我们小组的有机合成专家，我们将开发一条高效而模块化的路线 对小球素A.该合成策略的概念证明已经是 建立，并将促进cotylenin a合成的完成。小球蛋白核心将立即实现 基于现有晶体学数据生成类似物的多个位置的多样化。修改 在早期阶段的合成还将允许在其他站点进行基于结构的多样化，包括一个 这为实现PPI调制方面的特异性提供了一种新颖的手段。类似物的抗癌活性 我们还将进行蛋白质组学研究以识别 影响的蛋白质靶标。这些知识将指导cotylinin的迭代药物化学优化。 研究将在Scripps Research进行，该机构在合成化学和化学方面表现出色 生物学，并在两个领域建立了强大的合作。我将接受复杂分子的培训 该领域领导者Ryan Shenvi教授以及化学生物学培训的合成 生物学和蛋白质组学研究与Scripps Research的Chris Parker教授合作。这项工作是 在有机反应机制研究中，我的博士培训补充了。