A Structural Approach into Drug Discovery Based on Autophagy

Overview

Journal Life (Basel)

Specialty Biology

Date 2021 Jul 2

PMID 34199860

Authors

Sung-Min Kang

Do-Hee Kim

Affiliations

Soon will be listed here.

Abstract

Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.

References

He S, Li Q, Jiang X, Lu X, Feng F, Qu W . Design of Small Molecule Autophagy Modulators: A Promising Druggable Strategy. J Med Chem. 2017; 61(11):4656-4687. DOI: 10.1021/acs.jmedchem.7b01019. View

Klionsky D, Emr S . Autophagy as a regulated pathway of cellular degradation. Science. 2000; 290(5497):1717-21. PMC: 2732363. DOI: 10.1126/science.290.5497.1717. View

Mizushima N . The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol. 2010; 22(2):132-9. DOI: 10.1016/j.ceb.2009.12.004. View

Decaens T, Luciani A, Itti E, Hulin A, Roudot-Thoraval F, Laurent A . Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma. Dig Liver Dis. 2012; 44(7):610-6. DOI: 10.1016/j.dld.2012.02.005. View

Mizushima N, Komatsu M . Autophagy: renovation of cells and tissues. Cell. 2011; 147(4):728-41. DOI: 10.1016/j.cell.2011.10.026. View

Zhou X, Takatoh J, Wang F . The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation. PLoS One. 2011; 6(1):e16358. PMC: 3024421. DOI: 10.1371/journal.pone.0016358. View

Kitamura K, Kishi-Itakura C, Tsuboi T, Sato S, Kita K, Ohta N . Autophagy-related Atg8 localizes to the apicoplast of the human malaria parasite Plasmodium falciparum. PLoS One. 2012; 7(8):e42977. PMC: 3416769. DOI: 10.1371/journal.pone.0042977. View

Levine B, Mizushima N, Virgin H . Autophagy in immunity and inflammation. Nature. 2011; 469(7330):323-35. PMC: 3131688. DOI: 10.1038/nature09782. View

Ravikumar B, Sarkar S, Davies J, Futter M, Garcia-Arencibia M, Green-Thompson Z . Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010; 90(4):1383-435. DOI: 10.1152/physrev.00030.2009. View

10.

Sun D, Yang Z, Zhen Y, Yang Y, Chen Y, Yuan Y . Discovery of 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives as novel ULK1 inhibitors that block autophagy and induce apoptosis in non-small cell lung cancer. Eur J Med Chem. 2020; 208:112782. DOI: 10.1016/j.ejmech.2020.112782. View

11.

Xie W, Zhou J . Aberrant regulation of autophagy in mammalian diseases. Biol Lett. 2018; 14(1). PMC: 5803588. DOI: 10.1098/rsbl.2017.0540. View

12.

Huynh H, Chow K, Soo K, Toh H, Choo S, Foo K . RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med. 2008; 13(7):1371-80. PMC: 4496150. DOI: 10.1111/j.1582-4934.2008.00364.x. View

13.

Feldman R, Wu J, Polokoff M, Kochanny M, Dinter H, Zhu D . Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005; 280(20):19867-74. DOI: 10.1074/jbc.M501367200. View

14.

Pasquier B, El-Ahmad Y, Filoche-Romme B, Dureuil C, Fassy F, Abecassis P . Discovery of (2S)-8-[(3R)-3-methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: a novel potent and selective inhibitor of Vps34 for the treatment of solid tumors. J Med Chem. 2014; 58(1):376-400. DOI: 10.1021/jm5013352. View

15.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

16.

Villa S, Legnani L, Colombo D, Gelain A, Lammi C, Bongiorno D . Structure-based drug design, synthesis and biological assays of P. falciparum Atg3-Atg8 protein-protein interaction inhibitors. J Comput Aided Mol Des. 2018; 32(3):473-486. DOI: 10.1007/s10822-018-0102-5. View

17.

Yu H, Lin C, Tai W, Liu C, Shiau C, Chen K . Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. J Biol Chem. 2013; 288(25):18249-59. PMC: 3689967. DOI: 10.1074/jbc.M112.446385. View

18.

Tang F, Hu P, Yang Z, Xue C, Gong J, Sun S . SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways. Oncol Rep. 2017; 37(6):3449-3458. DOI: 10.3892/or.2017.5635. View

19.

Lazarus M, Shokat K . Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1. Bioorg Med Chem. 2015; 23(17):5483-8. PMC: 4864979. DOI: 10.1016/j.bmc.2015.07.034. View

20.

Peppard J, Rugg C, Smicker M, Dureuil C, Ronan B, Flamand O . Identifying Small Molecules which Inhibit Autophagy: a Phenotypic Screen Using Image-Based High-Content Cell Analysis. Curr Chem Genom Transl Med. 2014; 8(Suppl 1):3-15. PMC: 3941084. DOI: 10.2174/2213988501408010003. View