SCREENING ASSAY FOR COMPOUNDS TARGETING THE P97 AAA-ATPASE COMPLEX IN THE UBIQUITIN PROTEASOME SYSTEM.

摘要

A method and a cellular system for use in the screening process of compounds targeting the ubiquitin proteasome system (UPS), comprising several convergent protein degradation pathways. The invention especially relates to assays that allow high throughput screening of compounds that inhibit the AAA-ATPase p97 (VCP/CDC48) complex. It is anticipated that inhibitors of VCP, which are presently unavailable, will more specifically target the UPS in cancer cells. The invention provides a method to determine the efficacy and site of inhibitory action of chemical compounds on the UPS, primarily for use in chemical library screening processes. Hence, it provides methods to screen for compounds (small molecule, polypeptide, antibody, polynucleotide, organic or inorganic molecules, etc.) that inhibit or enhance the function of proteins in the UPS, which are required for pre-processing of substrates by the p97-complex. The invention also allows for determination of the applicability of similar compounds in disease states of interest related to this cellular pathway, which may contribute to define the next generation of pharmaceutical compounds in related fields of medicine.