High-Throughput Campaign to Identify Reversible Small Molecule Inhibitors of p97

The AAA ATPase p97 is a critical factor in maintaining protein homeostasis in eukaryotic cells. Two probe compounds ML240 and ML241 were developed that both inhibit p97 ATPase activity with an IC50 of approximately 100 nM, and block degradation of p97-dependent proteasome substrate with an IC50 of approximately 900 nM and 3500 nM, respectively. They specifically targeted p97, exhibited markedly different potencies for activating executioner caspases and blocking cell growth.