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

（宏观）自噬是一种主要的细胞内降解途径，介导清除长寿命或受损的蛋白质或细胞器。自噬发生在大多数细胞类型的基础水平，并确保细胞稳态。此外，在营养剥夺、生长因子停用、缺氧、化疗治疗或细胞内病原体感染等应激条件下，自噬也会被积极诱导。近年来，控制这一过程的分子机制已被确定和表征。由丝氨酸/苏氨酸激酶ULK1和相关蛋白ATG13、ATG101和RB1CC1组成的ULK1复合体是诱导自噬的核心元件。资助期的一个中心要素是该复合体内蛋白质-蛋白质相互作用的表征。有了这个更新建议，我们的目标是继续这些项目。我们打算建立小分子或肽模拟物，干扰ULK1复合物的蛋白-蛋白相互作用。确定的抑制剂将测试其自噬抑制/调节潜能。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。总之，我们想要确定的化合物是感兴趣的疾病的药物治疗，其中抑制自噬是需要的。

(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.