ArticleMolecular cancer2014
FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation.
Article in Molecular cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 72 citations in OpenAlex.
- Direct targeting of GLUT1 in cancer: A decade of inhibitor discovery and medicinal chemistry insights.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Disrupting the Hsp90-Cdc37 axis: a selective strategy for targeting oncogenic kinases in cancer.RSC advances · 2025Review
- Advances in the structures, mechanisms and targeting of molecular chaperones.Signal transduction and targeted therapy · 2025Review
- Total Synthesis of Tosyl-Samroiyotmycin A and Its Biological Profiling.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Article
- Discovery of new Hsp90-Cdc37 protein-protein interaction inhibitors:RSC advances · 2024Article
- [Risk modeling based on HER-2 related genes for bladder cancer survival prognosis assessment].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2023Article
- HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review).Oncology reports · 2023Review
- Rational design, synthesis and structural characterization of peptides and peptidomimetics to target Hsp90/Cdc37 interaction for treating hepatocellular carcinoma.Computational and structural biotechnology journal · 2023Article
- HSP90 mediates the connection of multiple programmed cell death in diseases.Cell death & disease · 2022Review
- Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity.Acta pharmacologica Sinica · 2022Article
- Modulation of Specialized Metabolite Production in Genetically EngineeredACS chemical biology · 2021Article
- Review
- Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity.Biomolecules · 2021Article
- The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition.Acta pharmaceutica Sinica. B · 2021Review
- Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling.Cancers · 2021Article
- Natural Occurrence of Hybrid Polyketides from Two Distinct Biosynthetic Pathways inACS chemical biology · 2021Article
- Synergistic Activity of the HSP90 Inhibitor Ganetespib With Lapatinib Reverses Acquired Lapatinib Resistance in HER2-Positive Breast Cancer Cells.Frontiers in pharmacology · 2021Article
- Conglobatins B-E: cytotoxic analogues of the CThe Journal of antibiotics · 2020Article
- Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery.Acta pharmaceutica Sinica. B · 2020Review
- Taxonomic Characterization and Secondary Metabolite Analysis of NEAU-wh3-1: AnMicroorganisms · 2020Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHeat shock protein 90 (Hsp90) is a promising therapeutic target and inhibition of Hsp90 will presumably result in suppression of multiple signaling pathways. FW-04-806, a bis-oxazolyl macrolide compound extracted from China-native Streptomyces FIM-04-806, was reported to be identical in structure to the polyketide Conglobatin.
methodsWe adopted the methods of chemproteomics, computational docking, immunoprecipitation, siRNA gene knock down, Quantitative Real-time PCR and xenograft models on the research of FW-04-806 antitumor mechanism, through the HER2-overexpressing breast cancer SKBR3 and HER2-underexpressing breast cancer MCF-7 cell line.
resultsWe have verified the direct binding of FW-04-806 to the N-terminal domain of Hsp90 and found that FW-04-806 inhibits Hsp90/cell division cycle protein 37 (Cdc37) chaperone/co-chaperone interactions, but does not affect ATP-binding capability of Hsp90, thereby leading to the degradation of multiple Hsp90 client proteins via the proteasome pathway. In breast cancer cell lines, FW-04-806 inhibits cell proliferation, caused G2/M cell cycle arrest, induced apoptosis, and downregulated Hsp90 client proteins HER2, Akt, Raf-1 and their phosphorylated forms (p-HER2, p-Akt) in a dose and time-dependent manner. Importantly, FW-04-806 displays a better anti-tumor effect in HER2-overexpressed SKBR3 tumor xenograft model than in HER2-underexpressed MCF-7 model. The result is consistent with cell proliferation assay and in vitro apoptosis assay applied for SKBR-3 and MCF-7. Furthermore, FW-04-806 has a favorable toxicity profile.
conclusionsAs a novel Hsp90 inhibitor, FW-04-806 binds to the N-terminal of Hsp90 and inhibits Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins. FW-04-806 displays promising antitumor activity against breast cancer cells both in vitro and in vivo, especially for HER2-overexpressed breast cancer cells.
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