Inhibition of the Human Proteasome by Imidazoline Scaffolds

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• 作者：Lauren M. Azevedo ; Theresa A. Lansdell ; Jacob R. Ludwig ; Robert A. Mosey ; Daljinder K. Woloch ; Dillon P. Cogan ; Gregory P. Patten ; Michael R. Kuszpit ; Jason S. Fisk ; Jetze J. Tepe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5974-5978
• 全文大小：321K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC₅₀ 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.