Targeting protein-protein interactions within the autophagy-inducing ULK1 complex for cancer therapy

靶向自噬诱导 ULK1 复合物内的蛋白质-蛋白质相互作用用于癌症治疗

• 批准号: 267192581
• 负责人: Professor Dr. Holger Gohlke
• 金额: --
• 依托单位: Institut für Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/267192581?language=en
• 关键词: Targeting; protein; interactions; within; autophagy

(Macro-)Autophagy is a major intracellular degradation pathway mediating the removal of long-lived or damaged proteins or organelles. Autophagy occurs at basal levels in most cell types and ensures cellular homeostasis. Additionally, autophagy is actively induced under stress conditions such as nutrient deprivation, growth factor withdrawal, hypoxia, treatment with chemotherapeutics, or infection with intracellular pathogens. In recent years, the molecular machinery governing this process has been identified and characterized. The ULK1 complex consisting of the Ser/Thr kinase ULK1 and the associated proteins ATG13, ATG101 and RB1CC1 represents a central element for the induction of autophagy. One central element of the funding period was the characterization of the protein-protein interactions within this complex. With this renewal proposal, we aim at consequently continuing these projects. We intend to establish small molecules or peptidomimetics that interfere with protein-protein interactions of the ULK1 complex. Identified inhibitors will be tested for their autophagy-inhibiting/modulating potential. In preclinical model systems, we will investigate the efficacy of these compounds either as monotherapies or in combination with established chemotherapeutics. In summary, we want to identify compounds that are of interest for the pharmacological therapy of diseases in which the inhibition of autophagy is desired.

(宏观)自噬是一种主要的细胞内降解途径，介导了长寿命或受损的蛋白质或细胞器的去除。在大多数细胞类型中，自噬发生在基础水平上，并确保细胞内环境的稳定。此外，自噬在应激条件下被积极诱导，如营养剥夺、生长因子停用、低氧、化疗药物治疗或感染细胞内病原体。近年来，控制这一过程的分子机制已经被识别和表征。由丝氨酸/苏氨酸蛋白激酶ULK1及其相关蛋白ATG13、ATG101和RB1CC1组成的ULK1复合体是诱导自噬的中心元件。资助期的一个核心要素是描述该复合体内蛋白质-蛋白质相互作用的特征。通过这项更新建议，我们的目标是因此继续这些项目。我们打算建立干扰ULK1复合体的蛋白质-蛋白质相互作用的小分子或多肽模拟物。已确定的抑制剂将被测试其自噬抑制/调节潜力。在临床前模型系统中，我们将研究这些化合物作为单一疗法或与现有化疗药物联合使用的疗效。综上所述，我们想要确定对抑制自噬的疾病的药物治疗感兴趣的化合物。