Targeting Cancer at the Protein-Membrane Interface

在蛋白质-膜界面靶向癌症

• 批准号: 10580562
• 负责人: Johannes Morstein
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580562
• 关键词: Address; Area; Binding; Biological; Biological Products; Cancer Biology; Cell Membrane Permeability; Cell membrane; Cells; Chemical Structure; Chemistry; Complement; Conceptions; Data; Development; Diffusion; Disease; Drug Design; Drug Targeting; Electrostatics; Endocytosis; Enzymes; Event; FRAP1 gene; G-Protein-Coupled Receptors; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Interdisciplinary Study; Ion Channel; KRAS2 gene; Lateral; Libraries; Link; Lipids; Liposomal Doxorubicin; MAP Kinase Gene; Malignant Neoplasms; Membrane; Membrane Proteins; Mentors; Mentorship; Methods; Natural Products; Nature; PIK3CG gene; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Process; Property; Proteins; RNA vaccine; Research; Role; Signal Pathway; Signal Transduction; Site; Structure-Activity Relationship; Testing; Training; WNT Signaling Pathway; anticancer research; biophysical properties; cancer immunotherapy; cancer pharmacology; cancer therapy; career; combinatorial; combinatorial chemistry; convict; design; drug discovery; experience; high throughput screening; holistic approach; inhibitor; innovation; insight; lipophilicity; nanotherapy; new therapeutic target; novel; novel strategies; pharmacologic; pharmacophore; receptor; recruit; screening; skills; small molecule; uptake

Project Summary Significant progress in human cancer therapy in the last decade has been driven by conceptionally new approaches to treating cancer, including cancer immunotherapy, cancer nanotherapy (e.g. liposomal doxorubicin or mRNA vaccines), or new types of biologics and small molecules. I propose to develop new approaches to targeting protein-membrane interactions that could yield unprecedented methods to modulate cancer signaling and generate useful paradigms for pharmacology at large. The role of protein-membrane and drug-membrane interactions will be explored and targeted on various levels, each highly relevant to cancer pharmacology: 1. Cancer signaling, a hallmark of cancer, is largely dependent on the recruitment of kinases (e.g. PI3K or PKC) and GTPases (e.g. RAS) to hotspots localized at the inner plasma membrane leaflet. I aim to develop bifunctional inhibitors with the capacity to modulate these interactions as a new approach to target cancer signaling. 2a. Membrane-integrated receptors are also key players in cellular signaling (e.g. enzyme-linked receptors or GPCRs). Recently, a number of pharmacophores have been discovered that target these proteins directly from the intramembrane space. These `Intramembrane pharmacophores' first partition into the membrane and then engage their target through lateral diffusion and entry. I aim to systematically modulate membrane exposed pharmacophore sites to explore principles governing the action of these pharmacophores which in turn will aid in the discoveries of new intramembrane pharmacophores. 2b. The majority of bioactive molecules acts on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. I propose to use combinatorial chemistry to discover new principles and chemical structures that modulate and privilege pharmacophores for cellular uptake. These will be tested in live cells using high throughput assays as a holistic approach to covering all possible uptake mechanisms on the first level of screening (e.g. endocytosis, transporters, passive diffusion). Combined, the proposed research will provide important insights into the functional role of protein- membrane interactions in cancer signaling and their vulnerability to small molecule-based modulation. Each of the proposed directions has the potential to yield fundamentally new and unprecedented approaches to targeting cancer and other diseases. My mentor and collaborators have extensive experience in cancer pharmacology, drug discovery, and the biophysical characterization of protein-membrane interfaces and will provide the training needed to conduct the proposed research. They will also provide the mentorship needed to acquire all skills and preliminary data needed for a successful transition to an independent career in cancer research.

项目概要 过去十年人类癌症治疗取得的重大进展是由新概念推动的 治疗癌症的方法，包括癌症免疫疗法、癌症纳米疗法（例如脂质体阿霉素 或 mRNA 疫苗），或新型生物制剂和小分子。我建议开发新方法 靶向蛋白质-膜相互作用，可能产生前所未有的调节癌症信号传导的方法 并为整个药理学产生有用的范例。蛋白质膜和药物膜的作用 将在各个层面上探索和瞄准相互作用，每个层面都与癌症药理学高度相关： 1. 癌症信号传导是癌症的一个标志，很大程度上取决于激酶（例如 PI3K 或 PKC）的招募 和 GTP 酶（例如 RAS）至位于内部质膜小叶的热点。我的目标是开发双功能 能够调节这些相互作用的抑制剂作为靶向癌症信号传导的新方法。 2a.膜整合受体也是细胞信号传导的关键参与者（例如酶联受体或 GPCR）。最近，已经发现许多药效团直接靶向这些蛋白质 膜内空间。这些“膜内药效团”首先进入膜，然后 通过横向扩散和进入来攻击他们的目标。我的目标是系统地调节膜暴露 药效团位点，探索控制这些药效团作用的原理，这反过来将有助于 发现新的膜内药效团。 2b.大多数生物活性分子作用于膜蛋白或细胞内靶标，因此需要 进入或穿过生物膜。我建议使用组合化学来发现新的 调节药效团并赋予细胞摄取特权的原理和化学结构。这些将 使用高通量检测作为涵盖所有可能吸收的整体方法在活细胞中进行测试 第一级筛选的机制（例如内吞作用、转运蛋白、被动扩散）。 结合起来，拟议的研究将为蛋白质的功能作用提供重要的见解。 癌症信号传导中的膜相互作用及其对小分子调节的脆弱性。 每个提出的方向都有可能产生全新的、前所未有的结果 针对癌症和其他疾病的方法。 我的导师和合作者在癌症药理学、药物发现和 蛋白质-膜界面的生物物理表征，并将提供进行所需的培训 提出的研究。他们还将提供获取所有技能和初步数据所需的指导 成功过渡到癌症研究独立职业所需的。