We describe a bis-benzylidine piperidone, RA190, which covalently binds to the
ubiquitin receptor RPN13 (ADRM1) in the 19S regulatory particle and inhibits
proteasome function, triggering rapid accumulation of polyubiquitinated proteins.
Multiple myeloma lines, even those resistant to
bortezomib, were sensitive to RA190 via ER stress-related
apoptosis. RA190 stabilized targets of
human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After p.o. or i.p. dosing of mice, RA190 distributed to
plasma and major organs excepting brain, and potently inhibited
proteasome function in
skin and
muscle. RA190 administration i.p. profoundly reduced growth of
multiple myeloma and
ovarian cancer xenografts, and oral RA190 treatment retarded HPV+ syngeneic
mouse tumor growth, without impacting spontaneous HPV-specific CD8+
T cell responses, suggesting its therapeutic potential. The bis-benzylidine piperidone RA190 is a new orally-available
proteasome inhibitor.
Multiple myeloma, cervical and ovarian cancers are particularly sensitive to RA190.