Identification and structural characterization of novel NPL4 inhibitors and insight into its mode of action

Inhibition of protein degradation via ubiquitin-proteasome system is promising approach to treat cancer as documented by activity of bortezomib against multiple myeloma, however, resistance and limited activity urges for new drugs. We have recently discovered that disulfiram-copper complex, a metabolite of Antabuse – a drug used to treat alcoholism, supress cancer cell growth via inhibition of NPL4 protein. NPL4 is an adaptor of p97 segregase, which is essential for recognition and delivery of ubiquitinated substrates dedicated for degradation in proteasome. Nevertheless, little is known about disulfiram-copper complex mode of binding and inhibition of NPL4 protein. Moreover, due to poor pharmacokinetic properties such as water insolubility of disulfiram-copper complex, new and more potent NPL4 inhibitors are desired. In this project, we propose to identify new NPL4 inhibitors and to extend our knowledge about their structural features and their mode of action towards NPL4 – new molecular target in cancer research