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

## TL;DR

Researchers discovered a small molecule, T1742, that inhibits key protein interactions in autophagy, potentially offering a new tool for studying or treating diseases.

## Contribution

T1742 is the first small-molecule inhibitor targeting ATG5-ATG16L1 and ATG5-TECAIR interactions.

## Key findings

- T1742 inhibits ATG5-ATG16L1 and ATG5-TECAIR interactions in vitro with low micromolar potency.
- T1742 effectively blocks autophagy in living cells in a dose-dependent manner.
- T1742 represents a new chemical tool for studying autophagy mechanisms and potential therapeutic applications.

## Abstract

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.