Targeting Wnt signaling pathway

靶向Wnt信号通路

基本信息

批准号：
10676662
负责人：
Jianfeng Cai
金额：
$ 42.62万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676662
关键词：
3-Dimensional Adopted Antineoplastic Agents Apoptosis B-Cell Lymphomas Binding Biological Assay Biological Process Biology Cell Proliferation Cells Chemicals Chemistry Complex DNA Data Development Disease Embryonic Development Foundations Future Generations Goals Growth Homeostasis Human Hyperactivity Immunoprecipitation In Vitro Inhibition of Cancer Cell Growth Knowledge Lead Learning Link Literature Medicine Modeling Modification Molecular Molecular Probes Mus Penetration Peptides Permeability Pharmaceutical Chemistry Play Proliferating Proteins Publications Reporting Resistance Reverse Transcriptase Polymerase Chain Reaction Role Secure Series Side Signal Pathway Signal Transduction Solid Specificity Spectrum Analysis Structure TCF Transcription Factor Tertiary Protein Structure Therapeutic Agents Transcriptional Activation Vertebral column WNT Signaling Pathway Work Xenograft Model alpha helix beta catenin cancer type cell growth cytotoxicity design embryo tissue improved in vivo inhibitor innovation meter mimetics novel novel anticancer drug novel strategies peptidomimetics protein complex protein protein interaction rational design scaffold small molecule subcutaneous targeted agent targeted treatment tumor tumor growth tumor progression tumor xenograft

项目摘要

Protein-protein interactions (PPIs) are increasingly important targets for bioorganic and medicinal chemistry, given the critical role of myriad protein complexes in vital biological processes including signal transduction, cell growth and proliferation, etc. Due to enhanced stability and functional diversity, helical peptidomimetics have emerged as a promising strategy for targeting PPIs, however their application is still limited as they generally do not mimic α-helices well owing to their difference in the three-dimensional helical structures. For instance, BCL9/β-catenin and TCF/β-catenin PPIs involved in Wnt signaling pathway play an important role in embryonic development and tissue homeostasis and are linked to several types of cancers. As such, molecules disrupting either BCL9/β-catenin or TCF/β-catenin PPIs could become novel anti-cancer agents by inhibiting Wnt/β-catenin signaling. However, the successful design of helical inhibitors based on unnatural scaffold to block the PPIs is previously unknown. We have recently developed a series of unprecedented helical sulfono-γ-AApeptides that can mimic α-helical domain of proteins. Given by the significance of β−catenin/BCL9 and TCF/β-catenin PPIs, we believe that mod- ulating these PPIs could serve as an excellent opportunity to formulate the general strategy for targeting any other PPIs involving α-helices. Compared to the BCL9 and TCF peptides not exhibiting cellular activity, our preliminary studies indicated that sulfono-γ-AApeptides not only can mimic these helical domains, but also are highly cell permeable and can selectively inhibit growth of cancer cells with hyperactive Wnt/β−catenin signaling. To the best of knowledge, our findings represents the first example of helical peptidomimetics based on unnatural backbone in disrupting these PPIs. As such, our long-term goal is to develop novel helical sulfono-γ-AApeptides that serve as proteolytically stable and cell-penetrating molecular entities capable of modulating a myriad of medicinally relevant PPIs. The objective here, is to establish the design strategy of sulfono-γ-AApeptides as helical domain mimetics to disrupt β−catenin/ BCL9 and TCF/β-catenin PPIs with optimal potency. We will first identify helical sulfono-γ-AApeptides that potently disrupt β−catenin/BCL9 and TCF/β-catenin PPIs in vitro. Fol- lowing that, we will confirm molecular mechanism of lead compounds is through modulation of Wnt signaling, by using confocal spectroscopy, TOPFlash and FOPFlash assay, cellular engagement assay, and related signaling assays to assess the selectivity, specificity and potency of these sequences on the cellular level. Finally, we will use a mouse tumor model to validate the ability of the inhibitors to inhibit Wnt signaling and tumor growth in vivo. The proposed work is significant, as these studies are highly likely to lead to a new generation of therapeutic agents targeting both β−catenin/BCL9 PPI and β-catenin/TCF PPIs, which will secure the goal of inhibiting Wnt signaling. The proposed work is innovative, because our strategy of protein-domain-mimicking using helical sulfono-γ-AApeptides is completely new and can be adopted to target myriad disease-related PPIs in the future.

蛋白质-蛋白质相互作用（PPI）是生物有机和药物化学日益重要的目标，鉴于无数蛋白质复合物在重要生物过程中的关键作用，包括信号转导、细胞生长和增殖等。由于增强的稳定性和功能多样性，螺旋肽模拟物已成为一种有前途的针对 PPI 的策略，但它们的应用仍然像通常那样受到限制由于三维螺旋结构的差异，它们不能很好地模仿α-螺旋，例如，参与Wnt信号通路的BCL9/β-catenin和TCF/β-catenin PPI在胚胎发育中发挥重要作用发育和组织稳态，并与多种类型的癌症有关。因此，分子破坏。 BCL9/β-catenin 或 TCF/β-catenin PPI 都可以通过抑制 Wnt/β-catenin 成为新型抗癌药物然而，成功设计基于非天然支架的螺旋抑制剂来阻断 PPI 仍是一个难题。以前未知。我们最近开发了一系列前所未有的螺旋磺基-γ-AA肽，可以模拟α-螺旋鉴于 β-catenin/BCL9 和 TCF/β-catenin PPI 的重要性，我们认为 mod- 制定这些 PPI 可以作为制定针对任何目标的总体战略的绝佳机会。与不涉及细胞活性的 BCL9 和 TCF 肽相比，我们的其他 PPI α-螺旋。初步研究表明磺基-γ-A肽不仅可以模拟这些螺旋结构域，而且还可以具有高度细胞渗透性，可以通过高度活跃的 Wnt/β-catenin 信号选择性抑制癌细胞的生长。据我们所知，我们的发现代表了基于非自然的螺旋肽模拟物的第一个例子因此，我们的长期目标是开发新型螺旋磺基-γ-A肽。作为蛋白水解稳定且细胞穿透的分子实体，能够调节多种医学相关的 PPI 的目标是建立磺基-γ-AA 肽的设计策略：我们将首先使用螺旋结构域模拟物来破坏 β−连环蛋白/ BCL9 和 TCF/β-连环蛋白 PPI。鉴定出可在体外有效破坏 β-catenin/BCL9 和 TCF/β-catenin PPI 的螺旋磺基-γ-A肽。由此，我们将确认先导化合物的分子机制是通过调节 Wnt 信号传导，通过使用共焦光谱、TOPFlash 和 FOPFlash 测定、细胞参与测定和相关信号传导最后，我们将评估这些序列在细胞水平上的选择性、特异性和效力。使用小鼠肿瘤模型来验证抑制剂在体内抑制 Wnt 信号传导和肿瘤生长的能力。拟议的工作意义重大，因为这些研究极有可能带来新一代的治疗方法同时针对β-catenin/BCL9 PPI和β-catenin/TCF PPI的药物，这将确保抑制Wnt的目标所提出的工作是创新的，因为我们使用螺旋模拟蛋白质结构域的策略。 sulfono-γ-AApeptides 是全新的，未来可用于靶向多种疾病相关的 PPI。