Working Paper Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 30 March 2021 / Approved: 31 March 2021 / Online: 31 March 2021 (15:30:27 CEST)

A peer-reviewed article of this Preprint also exists.

Siddiqui, F.A.; Vukic, V.; Salminen, T.A.; Abankwa, D. Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity. Biomolecules 2021, 11, 836. Siddiqui, F.A.; Vukic, V.; Salminen, T.A.; Abankwa, D. Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity. Biomolecules 2021, 11, 836.

Journal reference: Biomolecules 2021, 11, 836
DOI: 10.3390/biom11060836

Abstract

The natural product elaiophylin is a macrodiolide with broad 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 elaborate that elaiophylin likewise disrupts the Hsp90/ Cdc37 interaction, without affecting the ATP-pocket of Hsp90. Similar 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 3D spheroid formation. Finally, a strong inhibition of the same 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.

Keywords

K-Ras; Hsp90; Cdc37; nanoclustering; cancer; drug development

Subject

LIFE SCIENCES, Biochemistry

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