کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1356363 | 981111 | 2010 | 10 صفحه PDF | دانلود رایگان |

Elevated levels of activated Protein Kinase B (PKB/Akt) have been detected in many types of human cancer. In contrast to ATP site inhibitors, substrate-based inhibitors are more likely to be selective because of extensive interactions with the specific substrate binding site. Unfortunately, peptide-based inhibitors lack important pharmacological properties that are required of drug candidates. Chemical modifications of potent peptide inhibitors, such as peptoids and Nα-methylated amino acids, may overcome these drawbacks, while maintaining potency. We present a structure-activity relationship study of a potent, peptide-based PKB/Akt inhibitor, PTR6154. The study was designed to evaluate backbone modifications on the inhibitory activity of PTR6154. Two peptidomimetic libraries, peptoid and Nα-methylation, based on PTR6154, were synthesized and evaluated for in vitro PKB/Akt inhibition efficiency. All the peptoid analogs reduced potency significantly, as well as most of the members of the N-methyl library, suggesting that the backbone conformation and/or hydrogen bond interactions of PTR6154 derivatives are essential for inhibition activity. Two N-terminal members of the N-methyl library did not decrease potency and can be used as future drug leads.
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Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 8, 15 April 2010, Pages 2976–2985