General description:
CYTOMICS SYSTEMS’ protein degradation approach to drug discovery relies on UbiScreen®, a patented functional screening technology relevant to all targets regulated by the ubiquitin proteasome pathway. UbiScreen® allows the development of functional cell-based assays to monitor the degradation of specific protein targets. Implemented on the robotized HTS devices of the company, the UbiScreen technology currently allows the screening of ~4.000 molecules per day.
The company has assembled a team of highly qualified people with specialised skills and experience in protein degradation biochemistry, yeast molecular and cellular biology, human signalling biology, medicinal chemistry and preclinical studies.
Role in RUBICON:
There is compelling evidences that associate several classes of Human papillomaviruses (HPVs) with certain human anogenital cancer. More especially, HPVs are now recognized as the major cause of cervical cancers which cause the death of more than 400 000 women worldwide. “High risks” HPVs such as HPV16 and HPV18 encode small proteins, E6 and E7, which are now know to target the important cellular regulators, p53 and Rb, respectively. The steady state levels of the important tumour suppressor p53 protein was established to be abnormally low in HPV-carcinoma positive cells. Since it is widely believed that the stabilization and accumulation of p53 contribute to its growth suppressive properties, the cancer transformation of HPV positive cervical cells has been etiologically associated to p53 destabilization. It was further established that most of the activity of the oncoprotein E6 present in high-risk HPVs is the stimulation of the ubiquitin-mediated degradation of the p53 tumor suppressor protein. HPV E6 protein indeed triggers the pathological ubiquitin-dependent degradation of p53 by recruiting the cellular E6-AP ubiquitin ligase, a member of a family of HECT domain containing ubiquitin ligases. The objective of this project is to identify small molecules inhibiting the pathological degradation of p53 found in HPVs positive cervical cancer cells. This small molecules will be used to develop strategies to interrupt the process by which HPV infection can lead to the growth of abnormal cells. To identify these inhibitors, the approach is to implement the E6-dependent p53 degradation pathway in the yeast Saccharomyces cerevisiae. To establish this pathway, recombinant yeast cells lines will be constructed that conditionally express the three proteins, E6, E6AP and p53. The E6/E6AP-mediated destabilization of p53 in yeast cells will be measured through highly sensitive fluorescent methods. The process will be miniaturized and robotized, providing yeast cell lines that could be used to screen the highly diversified compound library of CYTOMICS SYSTEMS that currently comprises more than 70.000 different molecules. Secondary human cell based assays will be developed to further assess compound specificity.
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