Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling
| Autor: | Christina Oetken-Lindholm, Alok Jaiswal, Tero Aittokallio, Farid Ahmad Siddiqui, Vladimir R. Vukić, Hanna Parkkola, Tiina A. Salminen, Karolina Pavic, Alexandros Kiriazis, Daniel Abankwa |
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| Přispěvatelé: | Institute for Molecular Medicine Finland, University of Helsinki, Tero Aittokallio / Principal Investigator, Bioinformatics |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
3122 Cancers Context (language use) Hsp90 medicine.disease_cause lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine mental disorders polycyclic compounds medicine cancer Heat shock 030304 developmental biology 0303 health sciences biology Kinase Chemistry Cancer medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Small molecule drug development 3. Good health Cdc37 nanoclustering Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein KRAS K-Ras |
| Zdroj: | Cancers, Vol 13, Iss 927, p 927 (2021) Cancers Volume 13 Issue 4 |
| ISSN: | 2072-6694 |
| Popis: | The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened > 7 M compounds, and identified four novel small molecules with activities of 4 μM —44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases. |
| Databáze: | OpenAIRE |
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