Targeting autophagy in disease: established and new strategies.

ABSTRACT

Macroautophagy/autophagy is an evolutionarily conserved pathway responsible for clearing cytosolic aggregated proteins, damaged organelles or invading microorganisms. Dysfunctional autophagy leads to pathological accumulation of the cargo, which has been linked to a range of human diseases, including neurodegenerative diseases, infectious and autoimmune diseases and various forms of cancer. Cumulative work in animal models, application of genetic tools and pharmacologically active compounds, has suggested the potential therapeutic value of autophagy modulation in disease, as diverse as Huntington, Salmonella infection, or pancreatic cancer. Autophagy activation versus inhibition strategies are being explored, while the role of autophagy in pathophysiology is being studied in parallel. However, the progress of preclinical and clinical development of autophagy modulators has been greatly hampered by the paucity of selective pharmacological agents and biomarkers to dissect their precise impact on various forms of autophagy and cellular responses. Here, we summarize established and new strategies in autophagy-related drug discovery and indicate a path toward establishing a more efficient discovery of autophagy-selective pharmacological agents. With this knowledge at hand, modern concepts for therapeutic exploitation of autophagy might become more plausible.Abbreviations ALS amyotrophic lateral sclerosis; AMPK AMP-activated protein kinase; ATG autophagy-related gene; AUTAC autophagy-targeting chimera; CNS central nervous system; CQ chloroquine; GABARAP gamma-aminobutyric acid type A receptor-associated protein; HCQ hydroxychloroquine; LYTAC lysosome targeting chimera; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MTOR mechanistic target of rapamycin kinase; NDD neurodegenerative disease; PDAC pancreatic ductal adenocarcinoma; PE phosphatidylethanolamine; PIK3C3/VPS34 phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3K class III phosphatidylinositol 3-kinase; PtdIns3P phosphatidylinositol 3-phosphate; PROTAC proteolysis-targeting chimera; SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; SQSTM1/p62 sequestosome 1; ULK1 unc-51 like autophagy activating kinase 1.