Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones |
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| Institution: | 1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan;2. Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan;3. Graduate School of Pharmaceutical Sciences, University of Shizuoka, Yada, Shizuoka 422-8526, Japan;4. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan;1. Ufa Institute of Chemistry of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation;2. Institute of Petrochemistry and Catalysis of the Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation;1. Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu 061-0293, Japan;2. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan;1. Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan;2. Matsumoto Yushi-Seiyaku Co., Ltd, 2-1-3, Shibukawa-cho, Yao-City, Osaka 581-0075, Japan;1. Department of Physics, University of Pavia, Italy;2. National Institute of Nuclear Physics, INFN, Section of Pavia, Italy;3. Department of Chemistry ‘UgoSchi’ & CSGI, University of Florence, Florence, Italy;4. DISCAFF, University of Eastern Piedmont, Novara, Italy;5. Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche, Universit degli Studidi Pavia, Italy;1. Young Researchers and Elite Club, East Tehran Branch, Islamic Azad University, Tehran, Iran;2. Chemistry Department, Shahrood Branch, Islamic Azad University, Shahrood, Iran;3. Chemistry Department, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran;4. Center of Molecular and Materials Modelling, Hasselt University, Agoralaan, Gebouw D, B-3590 Diepenbeek, Belgium;1. Microbial Infection Group, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland;2. Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland;3. Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland;4. Trinity Centre for Bioengineering, Trinity College Dublin (TCD), College Green, Dublin 2, Ireland;5. Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin 2, Ireland;6. School of Pharmacy, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland |
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| 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. |
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| Keywords: | Proteasome inhibitor Epoxyketone Belactosin A |
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