A class of small molecule inhibitors active against HPV-related diseases
By protecting tumour-suppressing protein, small molecule inhibitors kill HPV-infected cancer cells
- Date : 02 May 2012
- Topic : Gynaecologic malignancies
Researchers at The Wistar Institute discovered small molecule inhibitors that kill cancer cells caused by infection with human papillomavirus (HPV). They presented their findings in the April 20 issue of the journal Chemistry & Biology, and believe that with further testing and refinement, their inhibitors could provide a therapeutic for HPV-caused tumours.
While there is an effective vaccine for preventing HPV infection, there is currently no therapeutic that specifically targets cancers caused by the virus, according to Ronen Marmorstein, PhD, senior author, and Dr Hilary Koprowski, Professor and leader of The Wistar Institute Cancer Centre Gene Expression and Regulation programme. The results, in both cell and mouse models, demonstrate that the small molecule inhibitors protect a tumour-suppressing protein targeted by viral proteins, thus killing the infected tumour cells.
Is this a start of an effective drug strategy for cancers caused by HPV?
HPV is one of the primary infectious causes of cancer, responsible for most cases of cervical cancer, nearly 20% of all head and neck cancers, and has been implicated in cancers of the vagina, penis, and anus. The USA Centres for Disease Control estimates that about 50% of sexually active men and women will be infected with HPV at one point in their lives. While most infected people will naturally fight off the infection, the virus frequently becomes latent, residing within the body for decades at a time. When HPV re-emerges from its latent state, it may cause host cells to become cancerous as the virus replicates.
New research has shown that the HPV protein, E7, targets an important tumour-suppressing protein - the retinoblastoma (pRb). When E7 binds to pRb, it disturbs the normal process of cell division, allowing the cells to grow out of control and unhindered and thus become cancerous.
In this latest study, the Wistar researchers describe the results of an exhaustive search for potential small molecule drug candidates to prevent E7 from binding to pRb. They screened a library of over 88,000 molecular compounds to find a class of small molecules that can prevent HPV-E7 from disabling pRb. Surprisingly, these inhibitors work by binding to pRb itself, yet do not seem to keep pRb from doing its normal job within the cell.
Once attached to pRb, these inhibitors allow pRb to trigger the molecular mechanisms of normal cell division without the disruptive effect of E7 upon HPV infection.
In subsequent studies, conducted with Associate Professor Joseph Kissil, PhD, of Wistar’s Molecular and Cellular Oncogenesis programme, one of these small molecule inhibitors proved effective in killing HPV-positive cells in mice.
Gaining a better molecular understanding on how to best refine new inhibitors so they are more effective and suitable for human use
The Marmorstein laboratory is currently involved in additional research towards developing inhibitors that block the ability of another key HPV protein - E6 to inactivate another important tumour suppressor - p53, a protein that is inactivated in the majority of human cancers. In addition, refinement of the HPV-E7 inhibitors is continuing. Their work will involve gaining a better molecular understanding of how their HPV-E7 inhibitors bind to pRb, which will enable them to make more informed decisions on how to best refine the inhibitors so that they are both more effective and suitable for human use.
Funding for this project was through the National Institutes of Health’s National Cancer Institute (USA).
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