Discovery of small-molecule inhibitors for the protein-protein interactions involving ATG5

The autophagy-related 12 (ATG12)-autophagy-related 5 (ATG5)-autophagy-related 16-like 1 (ATG16L1) ternary complex forms a dimer that facilitates the translocation of autophagy-related 8 (ATG8) proteins from autophagy-related 3 (ATG3) to phosphatidylethanolamine (PE). This event is fundamental for cargo sequestration and autophagy progression. Thus, one possible strategy for inhibiting autophagy is to disrupt the critical ATG5-ATG16L1 interaction during this process. So far very few known specific autophagy modulators can block autophagy effectively. We recently discovered a small-molecule compound, T1742, which is able to block the ATG5-ATG16L1 and ATG5-TECAIR interactions in vitro at the low-micromolar range (IC₅₀ = 1~2 μM). Flow cytometry assay and western blot experiments indicated that T1742 can also effectively inhibit autophagy in living cells in a dose-dependent manner. To the best of our knowledge, T1742 represents the first small-molecule autophagy inhibitor that disrupts the protein-protein interactions involving ATG5. Such compounds may serve as a new chemical tool for deciphering the mechanism of autophagy or a potential candidate for therapeutic application.