Original articles
Guodong Li, Joshua William Boyle, Chung-Nga Ko, Wu Zeng, Vincent Kam Wai Wong, Jian-Bo Wan, Philip Wai Hong Chan, Dik-Lung Ma, Chung-Hang Leung. Aurone derivatives as Vps34 inhibitors that modulate autophagy[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 537-544

Aurone derivatives as Vps34 inhibitors that modulate autophagy
Guodong Lia, Joshua William Boyleb, Chung-Nga Koc, Wu Zengd, Vincent Kam Wai Wongd, Jian-Bo Wana, Philip Wai Hong Chanb,e, Dik-Lung Mac, Chung-Hang Leunga
a State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China;
b School of Chemistry, Monash University, Clayton 3800, Australia;
c Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China;
d State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China;
e Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK
Abstract:
We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.
Key words:    Autophagy    Natural products    Vps34    Inhibitor    Structure-based virtual screening    Vesicle trafficking    Heart or liver damage    Aurone derivative   
Received: 2018-12-26     Revised:
DOI: 10.1016/j.apsb.2019.01.016
Funds: This work is supported by Hong Kong Baptist University (FRG2/16-17/007, FRG2/17-18/003, China), the Health and Medical Research Fund (HMRF/14150561, China), the Research Grants Council (HKBU/12301115, China), the National Natural Science Foundation of China (21575121 and 21775131, China), the Hong Kong Baptist University Century Club Sponsorship Scheme 2018 (China), the Interdisciplinary Research Matching Scheme (RC-IRMS/16-17/03, China), Interdisciplinary Research Clusters Matching Scheme (RC-IRCs/17-18/03, China), Innovation and Technology Fund (ITS/260/16FX, China), Matching Proof of Concept Fund (MPCF-001-2017/18, China), Collaborative Research Fund (C5026-16G, China), SKLEBA and HKBU Strategic Development Fund (SKLP_1718_P04, China), the Science and Technology Development Fund, Macao SAR (0072/2018/A2, China), the University of Macau (MYRG2016-00151-ICMS-QRCM and MYRG2018-00187-ICMS, China), and a Discovery Project Grant (DP160101682, Australia) from the Australian Research Council.
Corresponding author: Philip Wai Hong Chan, Dik-Lung Ma, Chung-Hang Leung     Email:phil.chan@monash.edu;edmondma@hkbu.edu.hk;duncanleung@um.edu.mo
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Authors
Guodong Li
Joshua William Boyle
Chung-Nga Ko
Wu Zeng
Vincent Kam Wai Wong
Jian-Bo Wan
Philip Wai Hong Chan
Dik-Lung Ma
Chung-Hang Leung

References:
1. Murrow L, Debnath J. Autophagy as a stress-response and qualitycontrol mechanism:implications for cell injury and human disease. Annu Rev Pathol-Mech Dis 2013;8:105-37.
2. Chen S, Dong G, Wu S, Liu N, Zhang W, Sheng C. Novel fluorescent probes of 10-hydroxyevodiamine:autophagy and apoptosis-inducing anticancer mechanisms. Acta Pharm Sin B 2019;9:144-56.
3. Kroemer G. Autophagy:a druggable process that is deregulated in aging and human disease. J Clin Investig 2015;125:1-4.
4. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013;19:983-97.
5. Doria A, Gatto M, Punzi L. Autophagy in human health and disease. N Engl J Med 2013;368:1845.
6. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069-75.
7. Bechtel W, Helmstädter M, Balica J, Hartleben B, Schell C, Huber TB. The class Ⅲ phosphatidylinositol 3-kinase PIK3C3/VPS34 regulates endocytosis and autophagosome-autolysosome formation in podocytes. Autophagy 2013;9:1097-9.
8. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, et al. Programmed cell death pathways in cancer:a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012;45:487-98.
9. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 2013;15:741-50.
10. Jaber N, Dou Z, Chen JS, Catanzaro J, Jiang YP, Ballou LM, et al. Class Ⅲ PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci U S A 2012;109:2003-8.
11. Jaber N, Dou Z, Lin RZ, Zhang J, Zong WX. Mammalian PIK3C3/VPS34:the key to autophagic processing in liver and heart. Autophagy 2012;8:707-8.
12. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008;27:5511-26.
13. Morris DH, Yip CK, Shi Y, Chait BT, Wang QJ. Beclin 1-Vps34 complex architecture:understanding the nuts and bolts of therapeutic targets. Front Biol 2015;10:398-426.
14. Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 2011;7:9-17.
15. Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, Shokat KM, et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 2010;327:1638-42.
16. Pasquier B. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy 2015;11:725-6.
17. Bilanges B, Vanhaesebroeck B. Cinderella finds her shoe:the first Vps34 inhibitor uncovers a new PI3K-AGC protein kinase connection. Biochem J 2014;464:e7-10.
18. Su WC, Chao TC, Huang YL, Weng SC, Jeng KS, Lai MM. Rab5 and class Ⅲ phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J Virol 2011;85:10561-71.
19. Yang C, Wang W, Chen L, Liang J, Lin S, Lee MY, et al. Discovery of a VHL and HIF1α interaction inhibitor with in vivo angiogenic activity via structure-based virtual screening. Chem Commun 2016;52:12837-40.
20. Zhong Z, Liu LJ, Dong ZQ, Lu L, Wang M, Leung CH, et al. Structure-based discovery of an immunomodulatory inhibitor of TLR1-TLR2 heterodimerization from a natural product-like database. Chem Commun 2015;51:11178-81.
21. Liu LJ, Leung KH, Chan DS, Wang YT, Ma DL, Leung CH. Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening. Cell Death Dis 2014;5:e1293.
22. Xiang YZ, Shang HC, Gao XM, Zhang BL. A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials. Phytother Res 2008;22:851-8.
23. Lachance H, Wetzel S, Kumar K, Waldmann H. Charting, navigating, and populating natural product chemical space for drug discovery. J Med Chem 2012;55:5989-6001.
24. Ronan B, Flamand O, Vescovi L, Dureuil C, Durand L, Fassy F, et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol 2014;10:1013-9.
25. Jiang X, Bao Y, Liu H, Kou X, Zhang Z, Sun F, et al. VPS34 stimulation of p62 phosphorylation for cancer progression. Oncogene 2017;36:6820-62.
26. Duran A, Amanchy R, Linares JF, Joshi J, Abu-Baker S, Porollo A, et al. p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 2011;44:134-46.
27. Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 2012;488:404-8.
28. San José-Enériz E, Agirre X, Rabal O, Vilas-Zornoza A, SanchezArias JA, Miranda E, et al. Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies. Nat Commun 2017;8:15424.
29. Futter CE, Collinson LM, Backer JM, Hopkins CR. Human VPS34 is required for internal vesicle formation within multivesicular endosomes. J Cell Biol 2001;155:1251-64.
30. Kang TS, Wang W, Zhong HJ, Dong ZZ, Huang Q, Mok SW, et al. An anti-prostate cancer benzofuran-conjugated iridium(Ⅲ) complex as a dual inhibitor of STAT3 and NF-κB. Cancer Lett 2017;396:76-84.
31. Wei Y, An Z, Zou Z, Sumpter R, Su M, Zang X, et al. The stressresponsive kinases MAPKAPK2/MAPKAPK3 activate starvationinduced autophagy through Beclin 1 phosphorylation. Elife 2015;4:e05289.
32. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-Ⅱ formation. J Cell Sci 2004;117:2805-12.
33. Zhang XJ, Chen S, Huang KX, Le WD. Why should autophagic flux be assessed?. Acta Pharmacol Sin 2013;34:595-9.
34. Jaber N, Zong WX. Class Ⅲ PI3K Vps34:essential roles in autophagy, endocytosis, and heart and liver function. Ann NY Acad Sci 2013;1280:48-51.
35. Zhong HJ, Ma VY, Cheng Z, Chan DH, He HZ, Leung KH, et al. Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening. Biochimie 2012;94:2457-60.
36. Ma DL, Chan DH, Wei G, Zhong HJ, Yang H, Leung LT, et al. Virtual screening and optimization of Type Ⅱ inhibitors of JAK2 from a natural product library. Chem. Commun 2014;50:13885-8.
37. Sujatha-Bhaskar S, Huang Z, Francis G, Bryan C, Zarrin AA, Kiefer J, et al. High throughput screening of IRAK4 small molecule inhibitors in TLR ligand stimulated whole blood. J. Immunol 2018;200:174-5.
38. Leung CH, Chan DSH, Kwan MHT, Cheng Z, Wong CY, Zhu GY, et al. Structure-based repurposing of FDA-approved drugs as TNF-α inhibitors. ChemMedChem 2011;6:765-8.