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

Min Jae Lee, Deepak Bhattarai, Jisu Yoo, Zach Miller, Ji Eun Park, Sukyeong Lee, Wooin Lee, James J. Driscoll, Kyung Bo Kim

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)4444-4455
Number of pages12
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
DOIs
StatePublished - May 9 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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