RA375, a RPN13 Inhibitor, Activates UPR Signaling, ROS Production and Apoptosis
Posted On 2020-07-21
Rpn13 is a known component of the proteasome. Especially, Rpn13 binds ubiquitin-like domains of the UBL/UBA family of ubiquitin receptors. Rpn13, as an ubiquitin receptor, offers a docking position for ubiquitinated substrate. RA375 is a RPN13 inhibitor.
Treatment with RA375 causes a rapid and profound accumulation of high molecular weight polyubiquitinated proteins. RA375 reduces intracellular glutathione levels, which produce endoplasmic reticulum and oxidative stress, and trigger apoptosis. RA375 is highly active against cell lines of multiple myeloma and diverse solid cancers. Furthermore, RA375 inhibits proteasome function in muscle for 72 h after single i.p. administration to mice, and treatment reduced tumor burden and extended survival in mice carrying an orthotopic human xenograft derived from a clear cell ovarian carcinoma.
The multiple myeloma lines are sensitive to RA375 treatment. Remarkably, RA375 exhibits ten-fold greater activity against the two cancer lines than RA190 in a competition assay. RA375 is efficacious against both the Bortezomib-resistant derivative lines and their parental lines. Moreover, RA375 shows similar potency in both a paclitaxel-resistant SKOV3 clone and its parental cell line. RA375 also potently inhibits triple-negative breast cancer and ovarian cancer cell colony formation. In addition, RA375 promotes the rapid onset of apoptosis in HPV16+ CaSki and SiHa and HPV18+ HeLa cells. RA375 induces a dramatic increase in bioluminescence, consistent with stabilization of 4UbFL, in a dose dependent manner. RA375 inhibits proteasome function and reduces ovarian tumor burden in mice.
In conclusion, RA375 is a potent RPN13 inhibitor. it emerges as a promising compound based on pharmacodynamics and its reduction of tumor burden and prolongation of the survival of mice carrying an orthotopic human ovarian cancer xenograft.