Elaiophylin Is a Potent Hsp90/Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity

被引:12
作者
Siddiqui, Farid A. [1 ,2 ]
Vukic, Vladimir [1 ,2 ,3 ]
Salminen, Tiina A. [4 ,5 ]
Abankwa, Daniel [1 ,2 ,6 ]
机构
[1] Univ Turku, Turku Biosci Ctr, Turku 20520, Finland
[2] Abo Akad Univ, Turku 20520, Finland
[3] Univ Novi Sad, Fac Technol, Novi Sad 21000, Serbia
[4] Abo Akad Univ, Fac Sci & Engn, Biochem, Struct Bioinformat Lab, Turku 20520, Finland
[5] Abo Akad Univ, InFLAMES Res Flagship Ctr, Turku 20520, Finland
[6] Univ Luxembourg, Dept Life Sci & Med, Canc Cell Biol & Drug Discovery Grp, L-4362 Esch Sur Alzette, Luxembourg
基金
芬兰科学院;
关键词
K-Ras; Hsp90; Cdc37; nanoclustering; cancer; drug development; EXERTS ANTITUMOR-ACTIVITY; MACRODIOLIDE FORMATION; AUTOPHAGY INHIBITOR; SMALL MOLECULES; H-RAS; HSP90; MECHANISM; ACTIVATION; MODEL; BLOCK;
D O I
10.3390/biom11060836
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The natural product elaiophylin is a macrodiolide with a broad range of biological activities. However, no direct target of elaiophylin in eukaryotes has been described so far, which hinders a systematic explanation of its astonishing activity range. We recently showed that the related conglobatin A, a protein-protein interface inhibitor of the interaction between the N-terminus of Hsp90 and its cochaperone Cdc37, blocks cancer stem cell properties by selectively inhibiting K-Ras4B but not H-Ras. Here, we elaborated that elaiophylin likewise disrupts the Hsp90/ Cdc37 interaction, without affecting the ATP-pocket of Hsp90. Similarly to conglobatin A, elaiophylin decreased expression levels of the Hsp90 client HIF1 alpha, a transcription factor with various downstream targets, including galectin-3. Galectin-3 is a nanocluster scaffold of K-Ras, which explains the K-Ras selectivity of Hsp90 inhibitors. In agreement with this K-Ras targeting and the potent effect on other Hsp90 clients, we observed with elaiophylin treatment a submicromolar IC50 for MDA-MB-231 and MIA-PaCa-2 3D spheroid formation. Finally, a strong inhibition of MDA-MB-231 cells grown in the chorioallantoic membrane (CAM) microtumor model was determined. These results suggest that several other macrodiolides may have the Hsp90/ Cdc37 interface as a target site.
引用
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页数:12
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