Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice

Background & aims: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on Cancer cells that do not express full-length P53, including many pancreatic Cancer cells. We searched for a compound that specifically inhibits MDM2 itself.

Methods: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic Cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice.

Results: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the Proteasome. The compound reduced levels of MDM2 in pancreatic Cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 μM (0.38-0.50 μM). Increasing concentrations of SP141 induced increasing levels of Apoptosis and G2-M-phase arrest of pancreatic Cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors.

Conclusions: In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic Cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 Inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic Cancer.