ArticleCancers2021
Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling.
Article in Cancers, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
12 citing papers in PubMed, 25 citations in OpenAlex.
- Article
- Proteomics- and BRET- screens identify SPRY2 as a Ras effector that impacts its membrane organization.iScience · 2025Article
- Heat Shock Proteins in Pancreatic Cancer: Pathogenic Mechanisms and Clinical Implications.Cells · 2025Review
- Disrupting the Hsp90-Cdc37 axis: a selective strategy for targeting oncogenic kinases in cancer.RSC advances · 2025Review
- Assessment of Hsp90β-selective inhibitor safety and on-target effects.Scientific reports · 2025Article
- Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies.Journal of hematology & oncology · 2024Review
- Identification of an H-Ras nanocluster disrupting peptide.Communications biology · 2024Article
- Review
- Small molecules targeting protein-protein interactions for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions.Biomolecules · 2022Review
- Review
- Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity.Biomolecules · 2021Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.