Abstract
The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV+-HNSCC) has increased dramatically over the past decades due to an increase in infection of the oral mucosa by HPV. The etiology of HPV+-HNSCC is linked to expression of the HPV oncoprotein, E6, which influences tumor formation, growth and survival. E6 effects this oncogenic phenotype in part through inhibitory protein-protein interactions (PPIs) and accelerated degradation of proteins with tumor suppressor properties, such as p53 and caspase 8. Interfering with the binding between E6 and its cellular partners may therefore represent a reasonable pharmacological intervention in HPV+ tumors. In this study, we probed a small-molecule library using AlphaScreen™ technology to discover novel E6 inhibitors. Following a cascade of screens we identified and prioritized one hit compound. Structure activity relationship (SAR) studies of this lead uncovered an analog, 30-hydroxygambogic acid (GA-OH), that displayed improved activity. Further testing of this analog in a panel of HPV+ and HPV– cell lines showed good potency and a large window of selectivity as demonstrated by apoptosis induction and significant inhibition of cell growth, cell survival in HPV+ cells. In summary, GA-OH may serve as a starting point for the development of potent E6-specific inhibitors.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are heterogeneous tumors that arise in the upper respiratory tract and are the 6th most common cancer worldwide by incidence
We screened 3 structurally diverse libraries (Prestwick library, Microsource Spectrum library and an in-house collection at Kansas University; see Supplementary Table 1) for the ability of compounds to inhibit the binding of full-length Human papillomavirus (HPV) E6 to human Caspase 8 using a previously optimized AlphaScreenTM protocol [22]
In our previous published work, we identified a number of flavonoid compounds as E6-specific inhibitors by probing smaller chemical compound libraries [22, 24]
Summary
Head and neck squamous cell carcinomas (HNSCC) are heterogeneous tumors that arise in the upper respiratory tract and are the 6th most common cancer worldwide by incidence. HPV--HNSCC, historically caused by chemical carcinogens such as alcohol and tobacco, has been in decline for the past 3 decades. For patients already presenting with HNSCC, current treatment guidelines recommend a combination approach involving surgery, radiation and chemotherapy, irrespective of the HPV status [7, 8]. This approach is not optimal, given the known distinct tumor biology and response to therapy. There has been a general consensus that the HPV+ subgroup may be overtreated and that selective therapies that spare patients from these long-term and deleterious side effects are needed
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