Discovery of aminopiperidine-based Smac mimetics as IAP antagonists
| Autor: | Naomi Laing, Nicholas A. Larsen, Jamal Carlos Saeh, Charles A. Omer, Haiyun Wang, Andrew D. Ferguson, Terry MacIntyre, Brian Aquila, Edward J. Hennessy, Li Sha |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Steric effects Clinical Biochemistry Pharmaceutical Science Inhibitor of apoptosis Biochemistry Inhibitor of Apoptosis Proteins Protein–protein interaction Mitochondrial Proteins Inhibitory Concentration 50 Structure-Activity Relationship Piperidines Biomimetics Cell Line Tumor Drug Discovery Humans Structure–activity relationship Amines Molecular Biology Molecular Structure Chemistry Organic Chemistry Intracellular Signaling Peptides and Proteins XIAP Cell culture Apoptosis Drug Design Cancer cell Molecular Medicine biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:1690-1694 |
| ISSN: | 0960-894X |
| Popis: | A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized. |
| Databáze: | OpenAIRE |
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