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Baek S Kutchukian PS Verdine GL Huber R Holak TA Lee KW Popowicz GM 《Journal of the American Chemical Society》2012,134(1):103-106
Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 ? resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface. 相似文献
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Synthesis of Complex Druglike Molecules by the Use of Highly Functionalized Bench‐Stable Organozinc Reagents
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Thomas J. Greshock Keith P. Moore Ray T. McClain Ana Bellomo Cheol K. Chung Spencer D. Dreher Peter S. Kutchukian Zhengwei Peng Ian W. Davies Petr Vachal Mario Ellwart Sophia M. Manolikakes Prof. Dr. Paul Knochel Philippe G. Nantermet 《Angewandte Chemie (International ed. in English)》2016,55(44):13714-13718
The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross‐coupling reactions was evaluated by high‐throughput experimentation protocols. The high‐fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug‐discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable‐space coverage. 相似文献
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