Development of p97 AAA ATPase inhibitors

Specific p97 inhibitors are valuable research tools to carry out mechanistic and cellular investigations of p97 biology. p97 is an abundant, ubiquitin-selective chaperone that has multiple functions and is essential for life. Therefore, genetic methods that require long incubations like siRNA or expression of dominant-negative p97 mutants are likely to generate complicated outcomes due to secondary consequences that arise upon slow depletion of p97 activity. We recently identified a small molecule p97 inhibitor, N(2),N(4)-dibenzylquinazoline-2,4-diamine (DBeQ), and documented its effects on blocking autophagic degradation of LC3-II and proteasomal degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. What distinguishes DBeQ from conventional proteasome inhibitors is that DBeQ affects both the UPS and autophagic protein degradation pathways and rapidly activates cell death. Whether DBeQ activates autophagic and/or apoptotic cell death will require further work to evaluate its detailed mechanism of action. An exciting goal for the future will be to generate p97 inhibitors that affect one or the other pathway. We propose that generation of 'separation of function' inhibitors will be a challenging adventure for chemical biologists but will yield extremely powerful tools to study p97 and enable evaluation of the therapeutic potential of targeting distinct p97 complexes.