Abstract A85: Discovery of highly potent and selective B-Raf Kinase inhibitors
| العنوان: | Abstract A85: Discovery of highly potent and selective B-Raf Kinase inhibitors |
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| المؤلفون: | Wang Xiaolun, Levin I. Jeremy, Nancy Torres, Donald Wojciechowicz, Edward J. Salaski, Yongbo Hu, Eileen Frommer, Dan Maarten Berger, Dennis Powell, Karen Collins |
| المصدر: | Molecular Cancer Therapeutics. 8:A85-A85 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | chemistry.chemical_classification, Cancer Research, Kinase, Cell, Wild type, Biology, Serine, Enzyme, medicine.anatomical_structure, Oncology, Biochemistry, chemistry, Cell culture, medicine, Signal transduction, Protein kinase A |
| الوصف: | B-Raf kinase, a serine/threonine protein kinase, is a component of RAS-Raf-MEK-ERK signaling pathway and plays a central role in cell growth and survival. B-Raf mutations have been found in about 8% of all cancers with the highest incidence in melanomas (66%). Thus a potent Raf inhibitor could have a significant impact in treating cancers that are dependent on this pathway for survival and proliferation signaling. As part of our program to prepare potent and structurally novel B-Raf kinase inhibitors, we designed a series of substituted pyrazolo[1,5- ]pyrimidines. Molecular modeling studies were utilized to validate the preparation of this series, as well as to optimize analogs to ultimately provide B-Raf inhibitors with subnanomolar IC50s. The modeling result also suggested these compounds bind to the active conformation of B-Raf. These pyrazolo[1,5- ]pyrimidine derivatives have moderate selectivity for B-Raf vs. C-Raf. Selected examples were screened for inhibition of a panel of 24 kinases and found to be highly selective. In addition to their enzymatic potency, the cell antiproliferative activities of these inhibitor were evaluated in B-Raf mutant cell lines (A375,WM266-4) and a cell line with wild type B-Raf (Caco-2). Selective inhibition of the B-Raf mutant cell lines with IC50 values less than 10 nM was observed for the most potent compounds. Finally, protein immunoblot analyses confirmed the inhibition of this MAPK signaling pathway by these analogs. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A85. |
| تدمد: | 1538-8514 1535-7163 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::524814e839cb0deb10ba60886cd95053Test https://doi.org/10.1158/1535-7163.targ-09-a85Test |
| رقم الانضمام: | edsair.doi...........524814e839cb0deb10ba60886cd95053 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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