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 de novo 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, 9,
harboring a hydroxyl substituent at its P1′ position was highly
cytotoxic against cancer cell lines displaying de novo 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.