Discovery of the Lysosome-Inhibiting Function of Acremolactone B
Shaonan Wang
1
School of Pharmacy, East China University of Science and Technology, Shanghai, China (Ringgold ID: RIN47860)
,
Yali Wu
1
School of Pharmacy, East China University of Science and Technology, Shanghai, China (Ringgold ID: RIN47860)
,
Mengyu Ba
2
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
Zhou Xu
2
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
Guoxing Gu
2
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
William G. Whittingham
3
Jealott’s Hill International Research Centre, Syngenta UK Ltd, Bracknell, United Kingdom of Great Britain and Northern Ireland (Ringgold ID: RIN10502)
,
Cong Liu
2
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
Lysosome inhibitors have garnered considerable interest for their utility in lysosome biology research and potential therapeutic applications. We discovered the lysosome-inhibiting function of acremolactone B (1), a scarce azaphilone-type polyketide, leveraging our previous scalable synthesis. This compound significantly reduces lysosomal acidity and impairs the maturation of the lysosomal protease cathepsin D (CTSD) in triple-negative breast cancer cells (MDA-MB-231) and human lung cancer cells (A549). Furthermore, we found that compound 1 suppresses downstream autophagy, as revealed by monitoring autophagic flux and conducting transmission electron microscopy (TEM) analysis. This study unveils the previously unrecognized biological role of 1 and introduces a new scaffold for lysosome inhibitors.
