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Study of Protein-protein Interactions in Autophagy Research
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Targeting the ATG12-ATG3 protein-protein interaction: From structural insights to therapeutic opportunities in

Emadeldin M Kamel1, Sally Mostafa Khadrawy2, Ahmed A Allam2

  • 1Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt.

Pathology, Research and Practice
|August 5, 2025
PubMed

Insights

Researchers developed small molecules to inhibit the ATG12-ATG3 interaction, a key step in autophagy. This disruption shows potential for treating cancer and inflammatory diseases by selectively silencing autophagy pathways.

Area of Science:

  • Biochemistry and Molecular Biology
  • Drug Discovery and Development
  • Cellular Biology

Background:

  • Autophagy is vital for cellular metabolism and immunity, but its dysregulation contributes to diseases like cancer and cytokine-storm syndromes.
  • The conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, mediated by the autophagy-related protein 3 (ATG3)-autophagy-related protein 12 (ATG12) interaction, is a critical step in autophagy.
  • Targeting the ATG12-ATG3 protein-protein interaction (PPI) offers a selective approach to modulate both degradative and secretory autophagy.

Purpose of the Study:

  • To review the development of inhibitors targeting the ATG12-ATG3 PPI, from initial structural insights to drug-like compounds.
  • To identify and optimize small molecules that selectively disrupt the ATG12-ATG3 interaction for therapeutic applications.
  • To explore the potential of ATG12-ATG3 inhibition in treating cancer, inflammatory conditions, and infectious diseases.

Main Methods:

  • High-resolution crystallography to determine the structural basis of the ATG12-ATG3 interaction, identifying key residues and binding motifs.
  • A high-throughput screening assay (split Gaussia luciferase) of over 40,000 compounds, guided by in-silico analysis, to identify initial disruptors.
  • Systematic structure-activity relationship (SAR) studies and medicinal chemistry efforts to optimize lead compounds, including developing an integrated assay toolbox (SPR, LC3 flux reporters) for potency and safety profiling.

Main Results:

  • Crystallography revealed an 'anchor-and-latch' motif in the ATG12-ATG3 interaction, characterized by a hydrophobic pocket ideal for small-molecule inhibition.
  • A lead compound (189) was identified and optimized, directly binding ATG12 with a KD of approximately 5 µM, collapsing autophagic flux and arresting tumor cell growth.
  • The optimized lead compound suppressed IL-1β secretion from macrophages without inducing kinase or lysosomal toxicity, demonstrating pathway selectivity and therapeutic potential.

Conclusions:

  • Small-molecule inhibitors targeting the ATG12-ATG3 interaction can selectively modulate autophagy, offering a promising therapeutic strategy.
  • Medicinal chemistry principles have been established to guide the design of potent and selective ATG12-ATG3 inhibitors.
  • Future directions include developing covalent-reversible chemotypes, PROTACs, and targeted delivery systems for first-in-class therapeutics in oncology, immunology, and infectious diseases.
Keywords:
ATG12-ATG3 interactionAutophagyCancer ImmunotherapyProtein-protein interaction disruptionSmall molecule inhibitors

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