Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/6/836 |
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| author | Farid A. Siddiqui Vladimir Vukic Tiina A. Salminen Daniel Abankwa |
| author_facet | Farid A. Siddiqui Vladimir Vukic Tiina A. Salminen Daniel Abankwa |
| author_sort | Farid A. Siddiqui |
| collection | DOAJ |
| description | 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 HIF1α, 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 IC<sub>50</sub> 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. |
| first_indexed | 2024-03-10T10:41:44Z |
| format | Article |
| id | doaj.art-2d8c2092bd934ab7affd11bf13ec7ff1 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T10:41:44Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-2d8c2092bd934ab7affd11bf13ec7ff12023-11-21T22:51:24ZengMDPI AGBiomolecules2218-273X2021-06-0111683610.3390/biom11060836Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster SelectivityFarid A. Siddiqui0Vladimir Vukic1Tiina A. Salminen2Daniel Abankwa3Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, FinlandTurku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, FinlandStructural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, FinlandTurku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, FinlandThe 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 HIF1α, 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 IC<sub>50</sub> 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.https://www.mdpi.com/2218-273X/11/6/836K-RasHsp90Cdc37nanoclusteringcancerdrug development |
| spellingShingle | Farid A. Siddiqui Vladimir Vukic Tiina A. Salminen Daniel Abankwa Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity Biomolecules K-Ras Hsp90 Cdc37 nanoclustering cancer drug development |
| title | Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity |
| title_full | Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity |
| title_fullStr | Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity |
| title_full_unstemmed | Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity |
| title_short | Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity |
| title_sort | elaiophylin is a potent hsp90 cdc37 protein interface inhibitor with k ras nanocluster selectivity |
| topic | K-Ras Hsp90 Cdc37 nanoclustering cancer drug development |
| url | https://www.mdpi.com/2218-273X/11/6/836 |
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