A Novel Proteasome Inhibitor (NPI-0052)

NPI-0052 is a novel proteasome inhibitor that was isolated from Salinispora tropica, a newly discovered marine actinomycete.  NPI-0052 is a bicyclic b-lactone g-lactam and therefore significantly differs structurally from other proteasome inhibitors in development that are peptide mimetics.  The structural differences apparently are important for the significant differences in proteasome inhibition, toxicology and efficacy profiles between these two classes of inhibitors.  NPI-0052 offers significant possibilities in the treatment of many cancers. Proteasome inhibition is thought to be selectively toxic to tumor cells through an accumulation of pro-apoptotic and anti-growth signal transduction pathway members, as well as the overabundant waste proteins produced by proliferating tumor cells (proteotoxicity). The success of Velcade, the first proteasome inhibitor approved by the FDA, in the treatment of multiple myeloma and mantle cell lymphoma provides evidence that proteasome inhibitors are effective clinically. However, resistance to Velcade and issues of toxicity provide significant opportunities for the development of a second generation proteasome inhibitor.  NPI-0052 is also a potent inhibitor of the 20S proteasome and, in in vitro studies, demonstrated faster, broader, longer and more potent inhibition than Velcade.   

NPI-0052 is active against multiple myeloma cells that are resistant to Velcade™, Revlimid™, Thalomid™ and steroids. The compound has also shown efficacy in animal models of multiple myeloma, colon, pancreatic and lung cancers when administered orally or intravenously as either a single agent or in combination with various biologics and chemotherapeutics, with a favorable toxicity profile.

Nereus' preclinical program for NPI-0052 involved experts in proteasome and translational biology, including Dr. Kenneth Anderson at the Dana Farber Cancer Institute, one of the leading clinicians responsible for the FDA approval of Velcade, and Dr. James Cusack at Massachusetts General Hospital, who described the synergistic activity of proteasome inhibitors with chemotherapeutics and their effects on NF-kB activity. Additional collaborators at MD Anderson, UCLA and other leading Universities  are further defining the mechanisms that mediate NPI-0052-induced anti-tumor activity  in various hematologic and solid tumor malignancies.  Demonstration of the advantages described above in these laboratory studies led to the initiation of clinical trials with NPI-0052 in 2006. NPI-0052 is currently being evaluated in multiple clinical trials as a single agent and in combination with Zolinza (SAHA, vorinostat), a histone deacetylase inhibitor (HDACi). Clinical page.

The  timeline for the discovery and development program for NPI-0052 is provide in the figure below.