Abstract 2918: Combining large scale biochemical and cellular profiling data to better understand the mechanism of anti-tumor drugs
| Autor: | Sharon Nauman, Jacob Bode, Lynn Byers, Blaine Armbruster, Clare Hadden |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:2918-2918 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2011-2918 |
| Popis: | This study was designed to elucidate the selectivity and cellular behavior of several marketed kinase inhibitors used in the treatment of cancer patients. Generally, kinase inhibitors are optimized to inhibit a single cellular target associated with cancer progression. However, most currently marketed kinase inhibitors interact with a highly conserved ATP binding site raising the question of their selectivity and therapeutic mechanism of action. Through EMD-Millipore's KinaseProfiler(TM) service, we functionally profiled the selectivity of Imatinib, Sunitinib, Lapatinib as well as several other marketed kinase inhibitors against a panel of over 250 kinases. Having identified the in vitro targets for these inhibitors, we next examined the potential of these small molecules to either directly inhibit several of the identified targets, or indirectly inhibit the activation of key signaling molecules downstream of these targets in several cell lines using EMD-Millipore's SignalProfiler(TM) service. Kinase profiling studies revealed that no kinase inhibitor was selective for a single target, with most inhibitors interacting with ten or more (sometimes phylogenetically distinct kinases) when tested at 1 µM. Additionally, several inhibitors were also found to either inhibit or activate certain GPCRs. The polypharmacology of the kinase inhibitors found through these studies would suggest that interaction with several molecular targets could contribute to either the therapeutic or adverse effects associated with these drugs. Current studies are underway to evaluate the cellular effect of these compounds to 1) resolve whether the compounds’ potential promiscuity, as revealed via biochemical studies, translates to a cellular context and 2) to assess whether drugs that share key therapeutic targets differentially affect cell signaling, due to differences in their off-target interactions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2918. doi:10.1158/1538-7445.AM2011-2918 |
| Databáze: | OpenAIRE |
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