Abstract C188: Novel small molecule inhibitors of p97 disrupt cellular protein homeostasis and demonstrate anti-tumor activity in solid and hematological models.

Abstract

Abstract Background: The ubiquitin-proteasome system (UPS) sustains cancer cell viability by alleviating proteotoxic stress caused by an imbalance of protein synthesis and degradation. Bortezomib and carfilzomib are 26S proteasome inhibitors approved for the treatment of multiple myeloma. Unfortunately, these agents have poor efficacy in solid tumors, prompting the need for discovery of novel drugs targeting other enzymes within the UPS. The AAA-ATPase p97/VCP functions by converting chemical energy into mechanical force and is closely involved in several facets of protein homeostasis. These include ubiquitin-dependent protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. p97 inhibition will provide a novel approach to exploit cancer cell addiction to protein homeostatic mechanisms. Results: Through a targeted medicinal chemistry effort, we have discovered novel small molecule inhibitors of p97 ATPase activity with nanomolar enzymatic and cellular potency. Sequencing of human cancer cell lines that have developed resistance to our p97 inhibitors has revealed mutations in p97, strongly suggesting on-target cellular activity. Treatment of normal and cancer cells with this class of p97 inhibitors causes a dramatic increase in poly-ubiquitinated proteins and an accumulation of substrates of the UPS and ERAD. These inhibitors also disrupt other specific p97 cellular functions including macroautophagy and receptor endocytosis. Inhibitor treatment ultimately leads to a blockade of NF-kB signaling and a decrease in downstream survival factors followed by the induction of caspase cleavage and apoptosis. In animal models, our p97 inhibitors are orally bio-available and cause rapid accumulation of poly-ubiquitin in tumor xenografts at levels that exceed the accumulation seen with bortezomib. Furthermore, significant tumor growth inhibition was observed in a number of solid tumor and hematological models. Conclusion: Together, these data provide novel insights into the role of p97 in cancer cell growth and the mechanism of death due to p97 inhibition. Animal model data suggests promise for our inhibitors as therapeutic agents for patients with hematological and solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C188. Citation Format: Stevan N. Djakovic, Daniel J. Anderson, Szerenke Kiss von Soly, Ronan Le Moigne, Julie Rice, Mark Rolfe, Ferdie Soriano, Eduardo Valle, Jinhai Wang, Steve Wong, David Wustrow, F. Michael Yakes, Bing Yao, Han-Jie Zhou. Novel small molecule inhibitors of p97 disrupt cellular protein homeostasis and demonstrate anti-tumor activity in solid and hematological models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C188.