Activity Enhancement of the Synthetic Syrbactin Proteasome Inhibitor Hybrid and Biological Evaluation in Tumor Cells
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- 作者：Crystal R. Archer ; Michael Groll ; Martin L. Stein ; Barbara Schellenberg ; J茅r么me Clerc ; Markus Kaiser ; Tamara P. Kondratyuk ; John M. Pezzuto ; Robert Dudler ; Andr茅 S. Bachmann
- 刊名：Biochemistry
- 出版年：2012
- 出版时间：August 28, 2012
- 年：2012
- 卷：51
- 期：34
- 页码：6880-6888
- 全文大小：400K
- 年卷期：v.51,no.34(August 28, 2012)
- ISSN：1520-4995
文摘
Syrbactins belong to a recently emergent class of bacterial natural product inhibitors that irreversibly inhibit the proteasome of eukaryotes by a novel mechanism. The total syntheses of the syrbactin molecules syringolin A, syringolin B, and glidobactin A have been achieved, which allowed the preparation of syrbactin-inspired derivatives, such as the syringolin A鈥揼lidobactin A hybrid molecule (SylA鈥揋lbA). To determine the potency of SylA鈥揋lbA, we employed both in vitro and cell culture-based proteasome assays that measure the subcatalytic chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities. We further studied the inhibitory effects of SylA鈥揋lbA on tumor cell growth using a panel of multiple myeloma, neuroblastoma, and ovarian cancer cell lines and showed that SylA鈥揋lbA strongly blocks the activity of NF-魏B. To gain more insights into the structure鈥揳ctivity relationship, we cocrystallized SylA鈥揋lbA in complex with the proteasome and determined the X-ray structure. The electron density map displays covalent binding of the Thr1Op>纬 p> atoms of all active sites to the macrolactam ring of the ligand via ether bond formation, thus providing insights into the structure鈥揳ctivity relationship for the improved affinity of SylA鈥揋lbA for the CT-L activity compared to those of the natural compounds SylA and GlbA. Our study revealed that the novel synthetic syrbactin compound represents one of the most potent proteasome inhibitors analyzed to date and therefore exhibits promising properties for improved drug development as an anticancer therapeutic.