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Bioorg Med Chem Lett. 2012 Mar 1;22(5):2125-9. doi: 10.1016/j.bmcl.2011.12.145. Epub 2012 Jan 10.

Small molecule inhibitors of the HPV16-E6 interaction with caspase 8.

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1
Department of Basic Sciences, Loma Linda University School of Medicine, 11085 Campus St., Loma Linda, CA 92354, USA.

Abstract

High-risk strains of human papillomaviruses (HPVs) cause nearly all cases of cervical cancer as well as a growing number of head and neck cancers. The oncogenicity of these viruses can be attributed to the activities of their two primary oncoproteins, E6 and E7. The E6 protein has among its functions the ability to prevent apoptosis of infected cells through its binding to FADD and caspase 8. A small molecule library was screened for candidates that could inhibit E6 binding to FADD and caspase 8. Flavonols were found to possess this activity with the rank order of myricetin>morin>quercetin>kaempferol=galangin≫(apigenin, 7-hydroxyflavonol, rhamnetin, isorhamnetin, geraldol, datiscetin, fisetin, 6-hydroxyflavonol). Counter screening, where the ability of these chosen flavonols to inhibit caspase 8 binding to itself was assessed, demonstrated that myricetin, morin and quercetin inhibited GST-E6 and His-caspase 8 binding in a specific manner. The structure-activity relationships suggested by these data are unique and do not match prior reports on flavonols in the literature for a variety of anticancer assays.

PMID:
22300659
PMCID:
PMC3288179
DOI:
10.1016/j.bmcl.2011.12.145
[Indexed for MEDLINE]
Free PMC Article
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