High-Throughput Campaign to Identify Reversible Small Molecule Inhibitor of p97/C

California Institute Of Technology, Pasadena CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): p97 is an essential protein that plays a critical role in a number of different cellular processes. This enzyme uses the energy released by hydrolysis of ATP to take apart assemblages of proteins and unfold individual polypeptides. A key cellular process in which p97 plays a critical role is in the degradation of proteins by the ubiquitin- proteasome system (UPS). Although there are abundant data to indicate that p97 plays a critical role in the UPS, the exact mechanism by which it works in protein turnover and the identity of its substrates largely remain unknown. It is particularly difficult to study the role of p97 in the UPS because p97 is essential, abundant, and involved in multiple other biological processes. The main approach to study protein function in human cells - depletion by RNA silencing - is rendered difficult by the abundance of p97. Moreover, as p97 is depleted, multiple cellular processes go awry and the cell begins to die, complicating the interpretation of experiments. For these reasons, we seek to identify a chemical compound that can be used to rapidly and reversibly inhibit the ATP hydrolysis activity of p97. The availability of such an inhibitor will allow in-depth exploration of the functions of p97 in normal and diseased human cells. PUBLIC HEALTH RELEVANCE: The ubiquitin-proteasome system (UPS) has been validated as a good target of cancer drugs by FDA approval of the proteasome inhibitor bortezomib for the treatment of multiple myeloma. Given that p97 is an essential protein that plays an important role in the UPS and is overproduced in multiple cancers, it is an intriguing target for the development of novel cancer drugs. Identification of a chemical compound that inhibits p97 will not only enable a deeper understanding of the function of this protein in normal and diseased cells (thereby shedding light on mechanisms of disease pathogenesis), but may also serve as a lead for the development of novel cancer drugs. [unreadable] [unreadable] [unreadable]