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Lee, Min Jae,Bhattarai, Deepak,Yoo, Jisu,Miller, Zach,Park, Ji Eun,Lee, Sukyeong,Lee, Wooin,Driscoll, James J.,Kim, Kyung Bo American Chemical Society 2019 Journal of medicinal chemistry Vol.62 No.9
<P>Over the past 15 years, proteasome inhibitors (PIs), namely bortezomib, carfilzomib (Cfz) and ixazomib, have significantly improved the overall survival and quality-of-life for multiple myeloma (MM) patients. However, a significant portion of MM patients do not respond to PI therapies. Drug resistance is present either <I>de novo</I> or acquired after prolonged therapy through mechanisms that remain poorly defined. The lack of a clear understanding of clinical PI resistance has hampered the development of next-generation PI drugs to treat MM patients who no longer respond to currently available therapies. Here, we designed and synthesized novel epoxyketone-based PIs by structural modifications at the P1′ site. We show that a Cfz analog, <B>9</B>, harboring a hydroxyl substituent at its P1′ position was highly cytotoxic against cancer cell lines displaying <I>de novo</I> or acquired resistance to Cfz. These results suggest that peptide epoxyketones incorporating P1′-targeting moieties may have the potential to bypass resistance mechanisms associated with Cfz and to provide additional clinical options for patients resistant to Cfz.</P> [FIG OMISSION]</BR>