Back to Search
Start Over
Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones.
- Source :
-
Bioorganic & Medicinal Chemistry . Jun2014, Vol. 22 Issue 12, p3091-3095. 5p. - Publication Year :
- 2014
-
Abstract
- Abstract: Proteasome inhibitors are currently a focus of increased attention as anticancer drug candidates. We recently performed systematic structure–activity relationship studies of the peptidic natural product belactosin A and identified non-peptidic derivative 2 as a highly potent proteasome inhibitor. However, the cell growth inhibitory effect of 2 is only moderate, probably due to the biologically unstable β-lactone warhead. Peptide epoxyketones are an important class of proteasome inhibitors exhibit high potency in cellular systems based on the efficient α,β-epoxyketone warhead. Importantly, belactosin derivatives bind primarily to the primed binding site, while peptide epoxyketones bind only to the non-primed binding site of proteasome, suggesting that hybridization of them might lead to the development of a new class of proteasome inhibitors. Thus, we successfully identified a novel chemotype of proteasome inhibitors 3 and 4 by rational structure-based design, which are expected to bind to both the primed and non-primed binding sites of proteasome. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 22
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 96020924
- Full Text :
- https://doi.org/10.1016/j.bmc.2014.04.032