RA190 is a potent Rpn13 inhibitor and ADRM1 Inhibitor, Suppressing Intrahepatic Cholangiocarcinoma by Inducing NF-kappaB-Mediated Cell Apoptosis. RA190 represents a novel class ofproteasome inhibitor that covalently binds to cysteine 88 of RPN13, an ubiquitin receptor subunit of the proteasome's 19S regulatory particle. RA190 treatment inhibitsproteasome function, causing rapid accumulation of polyubiquitinated proteins. RA190 has therapeutic activity in a xenograft model, and with sorafenib exhibited synergetic killing of HCC cells in vitro, suggesting further exploration of such a combination treatment of HCC is warranted.
RA190 forms a covalent bond with cysteine 88 on the RPN13 ubiquitin receptor within the 19S regulatory particle, leading to proteasome inhibition and a swift build-up of polyubiquitinated proteins. It is effective against multiple myeloma (MM) cell lines, including those that are bortezomib-resistant, by inducing apoptosis through endoplasmic reticulum stress. Additionally, RA190 impedes the degradation of human papillomavirus (HPV) E6 oncoprotein targets, resulting in the selective elimination of HPV-transformed cells[1].
RA190 动物研究
Animal study
RA190 is distributed throughout the plasma and most major organs, with the exception of the brain, and it disrupts proteasome activity in the skin and muscle. The administration of RA190 significantly diminishes the growth of multiple myeloma and ovarian cancer xenografts. Moreover, oral administration of RA190 slows down the growth of HPV16+ syngeneic mouse tumors without affecting the natural HPV-specific CD8+ T cell responses[1].
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