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

• Applicants: Professor Dr. Holger Gohlke; Professor Dr. Björn Stork
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267192581

(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.

• DFG Programme: Research Grants