2. Academic Validation
  3. Discovery of Small-Molecule Autophagy Inhibitors by Disrupting the Protein-Protein Interactions Involving Autophagy-Related 5

Discovery of Small-Molecule Autophagy Inhibitors by Disrupting the Protein-Protein Interactions Involving Autophagy-Related 5

  • J Med Chem. 2023 Feb 23;66(4):2457-2476. doi: 10.1021/acs.jmedchem.2c01233.
Honggang Xiang 1,  Ruiqi Liu 1,  Xiangying Zhang 1,  Ran An 2,  Mi Zhou 1,  Chang Tan 3 4,  Qing Li 4,  Minyi Su 4,  Chun Guo 2,  Lu Zhou 1,  Yingxia Li 1,  Renxiao Wang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
  • 2 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 3 Department of Chemistry, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China.
  • 4 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of China.
PMID: 36749313 DOI: 10.1021/acs.jmedchem.2c01233
Abstract

One possible strategy for modulating Autophagy is to disrupt the critical protein-protein interactions (PPIs) formed during this process. Our attention is on the autophagy-related 12 (ATG12)-autophagy-related 5 (ATG5)-autophagy-related 16-like 1 (ATG16L1) heterotrimer complex, which is responsible for ATG8 translocation from ATG3 to phosphatidylethanolamine. In this work, we discovered a compound with an (E)-3-(2-furanylmethylene)-2-pyrrolidinone core moiety (T1742) that blocked the ATG5-ATG16L1 and ATG5-TECAIR interactions in the in vitro binding assay (IC50 = 1-2 μM) and also exhibited Autophagy inhibition in cellular assays. The possible binding mode of T1742 to ATG5 was predicted through molecular modeling, and a batch of derivatives sharing essentially the same core moiety were synthesized and tested. The outcomes of the in vitro binding assay and the flow cytometry assay of those newly synthesized compounds were generally consistent. This work has validated our central hypothesis that small-molecule inhibitors of the PPIs involving ATG5 can tune down Autophagy effectively, and their pharmaceutical potential may be further explored.

Figures
Products