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

项目摘要 14-3-3蛋白质处于与癌症相关的多种细胞过程的十字路口，例如信号转导。 转导、细胞周期进程和凋亡。这个枢纽蛋白家族通过以下方式调节这些功能： 蛋白质-蛋白质相互作用（PPI）的扩展网络构成了14-3-3“相互作用组”。小 因此，14-3-3相互作用组的分子调节对于癌症治疗，特别是癌症治疗具有重要意义。 考虑到14-3-3蛋白在对标准护理药物的抗性中的作用。给14-3-3信号中心下药 使多个癌症相关过程受到干扰。虽然14-3-3 PPI的调节 仍然不发达，天然产品cotylenin A提供了一个分子平台来解决这个问题 缺陷Cotylenin A通过作为一种罕见的“分子胶”来稳定14-3-3/伴侣的相互作用。这是 被认为是Cotylenin A显著的抗癌活性和使癌细胞对现有的 治疗，同时保留正常细胞。此外，Cotylenin A的不常见结合模式具有优势， 提高药物选择性和降低功效所需的亲和力。然而，Cotylenin A并没有被 由于天然来源的损失和缺乏有效的和容易多样化的合成，开发作为治疗剂。 该提案旨在通过化学疗法来促进基于cotylenin的癌症疗法的发展。 合成.利用我们集团在有机合成方面的专业知识，我们将开发一种高效和模块化的路线 到Cotylenin A.这种合成策略的概念证明已经进入了Cotylenin核心。 建立，并将促进完成cotylenin A的合成。Cotylenin核心可以立即 基于现有的晶体学数据，在几个位置进行多样化以产生类似物。修改 在早期阶段的合成也将允许在其他地点，包括一个基于结构的多样化 这提供了一种新的方法来实现PPI调节的特异性。类似物的抗癌活性 将进行评价，以阐明结构-活性关系。我们还将进行蛋白质组学研究， 受影响的蛋白质目标。这些知识将指导迭代的药物化学优化的cotylenins。 研究将在斯克里普斯研究所进行，该研究所擅长合成化学和化学 生物学，并促进两个领域的密切合作。我将接受复杂分子方面的培训 Ryan Shenvi教授的合成，该领域的领导者，以及通过执行化学生物学培训 与Scripps Research的Chris帕克教授合作进行生物学和蛋白质组学研究。这项工作是 这是对我在有机金属反应机理研究方面的博士训练的补充。

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.