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Abstract
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.

Author information

Lee MJ1, Bhattarai D1, Yoo J2, Miller Z1, Park JE2, Lee S3, Lee W2, Driscoll JJ4, Kim KB1.
1
Department of Pharmaceutical Sciences , University of Kentucky , Lexington , Kentucky 40536 , United States.
2
College of Pharmacy and Research Institute of Pharmaceutical Sciences , Seoul National University , Seoul 08826 , Korea.
3
Verna and Marrs McLean Department of Biochemistry and Molecular Biology , Baylor College of Medicine , Houston , Texas 77030 , United States.
4
Department of Internal Medicine , Division of Hematology and Oncology and University of Cincinnati Cancer Institute , Cincinnati , Ohio 45267 , United States.