Reference : Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanoclust...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/50611
Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity
English
Siddiqui, Farid A. [Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland]
Vukic, Vladimir [Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland > > > ; Faculty of Technology, University of Novi Sad, 21000 Novi Sad, Serbia]
Salminen, Tiina A. [Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland > > > ; InFLAMES Research Flagship Center, Åbo Akademi University, 20520 Turku, Finland]
Abankwa, Daniel mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
4-Jun-2021
Biomolecules
Multidisciplinary Digital Publishing Institute (MDPI)
Yes
International
2218-273X
Switzerland
[en] K-Ras ; Hsp90 ; Cdc37
[en] 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 , 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 MIAPaCa-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.
Academy of Finland (#304638) and the Jane and Aatos Erkko Foundation, Finland
Researchers
http://hdl.handle.net/10993/50611
10.3390/biom11060836

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