A series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2010.06.068 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
From Genes to Metabolites: HSP90B1's Role in Alzheimer's Disease and Potential for Therapeutic Intervention.
Neuromolecular Med
January 2025
Department of Neurology, Second Affiliated Hospital of Army Medical University (Xinqiao Hospital), Chongqing, China.
Alzheimer's disease (AD) is a prototypical neurodegenerative disorder, predominantly affecting individuals in the presenile and elderly populations, with an etiology that remains elusive. This investigation aimed to elucidate the alterations in anoikis-related genes (ARGs) in the AD brain, thereby expanding the repertoire of biomarkers for the disease. Using publically available gene expression data for the hippocampus from both healthy and AD subjects, differentially expressed genes (DEGs) were identified.
View Article and Find Full Text PDFLanosterol 14α-Demethylase (CYP51)/Heat Shock Protein 90 (Hsp90) Dual Inhibitors for the Treatment of Invasive Candidiasis.
J Med Chem
January 2025
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, China.
Invasive candidiasis has attracted global attention with a high incidence and mortality. Current antifungal drugs are limited by unfavorable therapeutic efficacy, significant hepatorenal toxicity, and the development of drug resistance. Herein, we designed the first generation of lanosterol 14α-demethylase (CYP51)/heat shock protein 90 (Hsp90) dual inhibitors on the basis of antifungal synergism.
View Article and Find Full Text PDFHSP90 stabilizes visual cycle retinol dehydrogenase 5 in the endoplasmic reticulum by inhibiting its degradation during autophagy.
J Biol Chem
December 2024
The Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology, The Joint National Laboratory of Antibody Drug Engineering, Henan Province Engineering Research Center of Fundus Disease and Ocular Trauma Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China; Kaifeng Key Lab for Cataracts and Myopia, Kaifeng Central Hospital, Kaifeng, China; Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, China. Electronic address:
Genetic mutations in retinol dehydrogenase 5 (RDH5), a rate-limiting enzyme of the visual cycle, is associated with nyctalopia, AMD and stationary congenital fundus albipunctatus (FA). A majority of these mutations impair RDH5 protein expression and intracellular localization. However, the regulatory mechanisms underlying RDH5 metabolism remain unclear.
View Article and Find Full Text PDFAnticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma.
Mol Cell Biol
December 2024
Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity.
View Article and Find Full Text PDFCell Membrane Hybrid Liposome-Targeted Delivery of the Heat Shock Protein 90 C-Terminal Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis.
ACS Pharmacol Transl Sci
December 2024
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Idiopathic pulmonary fibrosis (IPF) represents a grave challenge as it is characterized by high fatality rates and irreversible progression without effective clinical interventions available at present. Previous studies have demonstrated that inhibition of heat shock protein 90 (HSP90) by an N-terminal inhibitor disrupts its interaction with TGFβRII, leading to the instability of TGFβRII, thus blocking the role of transforming growth factor-β1 (TGF-β1), which could potentially ameliorate IPF symptoms. However, given that the broad spectrum of HSP90 N-terminal inhibitors may lead to unanticipated side effects, we hypothesize that C-terminal inhibitors of HSP90 can interfere with TGFβRII while minimizing adverse reactions.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!