Bis-benzylidine piperidone proteasome inhibitor with anticancer activity
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United States of America Patent
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Mar 13, 2018
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app pub date -
May 6, 2014
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May 8, 2013
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Abstract
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.
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- THE JOHNS HOPKINS UNIVERSITY
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Inventor Name | Address | # of filed Patents | Total Citations |
---|---|---|---|
Anchoori, Ravi K | Elkridge, US | 4 | 7 |
Karanam, Balasubramanyam | Auburn, US | 2 | 7 |
Roden, Richard B | Severna Park, US | 5 | 32 |
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