Abstract 4941: Development of small molecule RPN13 inhibitors for treatment of glioblastoma

Abstract

Abstract Glioblastoma (GBM) is an aggressive and deadly brain cancer with a one-year median survival due to the lack of effective targeted treatments. Our goal is to develop a small molecule inhibitor targeting RPN13 protein in the 19S proteasome complex as a new drug for GBM. RPN13 is a proteasome ubiquitin receptor that recognizes ubiquitin-conjugated proteins that are thus tagged for degradation via the 20S proteasome enzymatic complex. GBM is highly sensitive to proteasome inhibition due to its aggressive growth and accumulation of misfolded polyubiquitinated proteins that is insufficiently managed despite increased proteasome levels and enhanced proteasome activity (i.e. proteotoxic stress). Up Therapeutics judiciously designed drug-like RPN13 inhibitors to overcome limitations in the prototype RPN13 inhibitor RA190 identified at Johns Hopkins University. We selected Up284 as lead compound based upon our preliminary studies showing drug-like characteristics, specificity (binding to Cys88 of RPN13), and proteasome inhibition that produces a cytotoxic accumulation of polyUb proteins, ER stress, and reactive oxygen species. Up284 treatment selectively triggers apoptosis in solid tumor types including GBM cell lines and oncospheres. A suitable Up284 formulation was selected by measuring aqueous solubility, stability and on-target activity in mice imaged using a proteasome-dependent in vivo reporter. Up284 can be administered i.v. or orally, and it penetrates through the BBB. As a proof of concept for treatment of GBM, Up284 demonstrated on-target activity in intracranial syngeneic GL261 tumor model by inhibiting proteasome function in tumor tissues. Up284 also well tolerated and regressed tumors in syngeneic, xenograft and spontaneous models of ovarian and breast cancers with acceptable safety profile. Up284 also synergize with current frontline chemotherapeutics and can be used as a single agent or in combination for the treatment of wide range of cancers. Citation Format: Yung-Nien Chang, Ravi K. Anchoori, Alex Shimura Yamashita, Marina da Costa Rosa. Development of small molecule RPN13 inhibitors for treatment of glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4941.