Development of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib.

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.

• Authors: Min Jae Lee, Deepak Bhattarai, Jisu Yoo, Zach Miller, Ji Eun Park, Sukyeong Lee, Wooin Lee, James J Driscoll, Kyung Bo Kim
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 9 Pg. 4444-4455 (05 09 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30964987 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Epoxy Compounds
• Ketones
• Oligopeptides
• Peptides
• Proteasome Inhibitors
• Bortezomib
• carfilzomib

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Bortezomib (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Drug Stability
• Epoxy Compounds (chemical synthesis, metabolism, pharmacology)
• Humans
• Ketones (chemical synthesis, metabolism, pharmacology)
• Male
• Molecular Docking Simulation
• Oligopeptides (pharmacology)
• Peptides (chemical synthesis, metabolism, pharmacology)
• Proteasome Inhibitors (chemical synthesis, metabolism, pharmacology)
• Rats, Sprague-Dawley