Open AccessDevelopment of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib
Author(s) -
Minjae Lee,
Deepak Bhattarai,
Jisu Yoo,
Zach Miller,
Ji Eun Park,
Sukyeong Lee,
Wooin Lee,
James J. Driscoll,
Kyung Bo Kim
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b01943
Subject(s) - carfilzomib , ixazomib , bortezomib , proteasome inhibitor , chemistry , proteasome , pharmacology , multiple myeloma , drug resistance , cancer research , cancer , medicine , biology , biochemistry , microbiology and biotechnology
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.