Abstract DDT02-01: Inhibition of the AAA-ATPase p97 with the first in class inhibitor CB-5083 as a novel approach to treat cancer
Authors: Daniel J. Anderson, Ronan Le Moigne, Stevan Djakovic, Brajesh Kumar, Julie Rice, Steve Wong, Jinhai Wang, Bing Yao, Eduardo Valle, MK Menon, Szerenke Kiss von Soly, Antonett Madriaga, Ferdie Sorlano, Mike Longhi, Alessandra Cesano, Han-Jie Zhou, David Wustrow, Mark Rolfe
Journal: Cancer Research (2015)

Abstract The ubiquitin-proteasome system (UPS) sustains cancer cell viability by alleviating proteotoxic stress caused by an imbalance of protein synthesis and degradation. While proteasome inhibitors and immunomodulators (IMiDs) are approved for the treatment of hematological malignancies, relapse following treatment is common. Additionally, these agents have poor efficacy in solid tumors, prompting the need for discovery of novel drug targets within the UPS which might provide a more profound anti-tumor effect. The homo-hexameric AAA-ATPase VCP/p97 functions by converting chemical energy into mechanical force to extract proteins from cell membranes and protein complexes. p97 is directly involved in several facets of protein homeostasis, including ubiquitin-dependent protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Therefore p97 inhibition could provide a novel and more potent approach than proteasome inhibitors to exploit cancer cell addiction to protein homeostatic mechanisms. Through a targeted medicinal chemistry effort we have discovered CB-5083, a novel small molecule ATP-competitive inhibitor of p97 ATPase activity with nanomolar enzymatic and cellular potency. Treatment of cancer cells with CB-5083 causes a dramatic increase in poly-ubiquitinated proteins and an accumulation of substrates of the UPS and ERAD. The blockade of ERAD causes induction of an irresolvable unfolded protein response (UPR), leading to caspase cleavage and apoptosis in a manner that is distinct from proteasome inhibitors. Indeed, ER-related stress and ERAD genes were the most significantly upregulated gene ontologies uncovered from transcriptome profiling. Additionally, knockdown of DR5 protects against CB-5083 mediated cell death, suggesting that death receptor signaling plays a key role in the apoptotic response caused by inhibition of p97 function. In animal models, our p97 inhibitor is orally bio-available and causes rapid and sustained accumulation of poly-ubiquitin and markers of the UPR and apoptosis. Furthermore, strong anti-cancer effects were observed in solid tumor and hematological murine models. We have developed a clinical-grade multiparametric flow cytometry assay to measure the accumulation of lysine-48 linked poly-ubiquitin and cPARP from human whole blood and circulating multiple myeloma cells, providing a way to monitor changes to the UPS and biological activity in real time. CB-5083 is currently being tested in ongoing phase I clinical trials for relapsed/refractory multiple myeloma and solid tumor patients. Taken together, these results indicate that CB-5083 has great promise as a novel therapeutic agent for the treatment of cancer. Citation Format: Daniel J. Anderson, Ronan Le Moigne, Stevan Djakovic, Brajesh Kumar, Julie Rice, Steve Wong, Jinhai Wang, Bing Yao, Eduardo Valle, MK Menon, Szerenke Kiss von Soly, Antonett Madriaga, Ferdie Sorlano, Mike Longhi, Alessandra Cesano, Han-Jie Zhou, David Wustrow, Mark Rolfe. Inhibition of the AAA-ATPase p97 with the first in class inhibitor CB-5083 as a novel approach to treat cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2015-DDT02-01