Discovery of a Highly Specific and Potent Pan-RAF Inhibitor
We describe the structure‐based design and synthesis of N‐(2,6‐difluorophenyl)‐3‐(9H‐purin‐6‐yl)pyridine‐2‐amine derivatives as a selective pan‐RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N‐(3‐((3‐(9H‐pur...
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| Published in | Bulletin of the Korean Chemical Society Vol. 37; no. 10; pp. 1632 - 1637 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Weinheim
Wiley-VCH Verlag GmbH & Co. KGaA
01.10.2016
Wiley‐VCH Verlag GmbH & Co. KGaA 대한화학회 |
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| Online Access | Get full text |
| ISSN | 1229-5949 0253-2964 1229-5949 |
| DOI | 10.1002/bkcs.10917 |
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| Abstract | We describe the structure‐based design and synthesis of N‐(2,6‐difluorophenyl)‐3‐(9H‐purin‐6‐yl)pyridine‐2‐amine derivatives as a selective pan‐RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N‐(3‐((3‐(9H‐purin‐6‐yl)pyridine‐2‐yl)amino)‐2,4‐difluorophenyl)furan‐3‐sulfonamide (4b) exhibited the most potent inhibitory activities against protein kinase enzymes BRAFV600E, BRAFWT, and CRAF (IC50 of 2, 2, and 1 nM, respectively) and a mutant cell line bearing a BRAFV600E mutation, A375P (GI50 of 7 nM). |
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| AbstractList | We describe the structure‐based design and synthesis of N‐(2,6‐difluorophenyl)‐3‐(9H‐purin‐6‐yl)pyridine‐2‐amine derivatives as a selective pan‐RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N‐(3‐((3‐(9H‐purin‐6‐yl)pyridine‐2‐yl)amino)‐2,4‐difluorophenyl)furan‐3‐sulfonamide (4b) exhibited the most potent inhibitory activities against protein kinase enzymes BRAFV600E, BRAFWT, and CRAF (IC50 of 2, 2, and 1 nM, respectively) and a mutant cell line bearing a BRAFV600E mutation, A375P (GI50 of 7 nM). We describe the structure-based design and synthesis of N-(2,6-difluorophenyl)-3-(9H-purin-6-yl)pyridine-2-amine derivatives as a selective pan-RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N-(3-((3-(9H-purin-6-yl)pyridine-2-yl)amino)-2,4-difluorophenyl)furan-3-sulfonamide (4b) exhibited the most potent inhibitory activities against protein kinase enzymes BRAFV600E, BRAFWT, and CRAF (IC50 of 2, 2, and 1 nM, respectively) and a mutant cell line bearing a BRAFV600E mutation, A375P (GI50 of 7 nM). KCI Citation Count: 0 We describe the structure‐based design and synthesis of N ‐(2,6‐difluorophenyl)‐3‐(9 H ‐purin‐6‐yl)pyridine‐2‐amine derivatives as a selective pan‐ RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAF V600E mutant cell line. Among them, N ‐(3‐((3‐(9 H ‐purin‐6‐yl)pyridine‐2‐yl)amino)‐2,4‐difluorophenyl)furan‐3‐sulfonamide ( 4b ) exhibited the most potent inhibitory activities against protein kinase enzymes BRAF V600E , BRAF WT , and CRAF ( IC 50 of 2, 2, and 1 nM , respectively) and a mutant cell line bearing a BRAF V600E mutation, A375P ( GI 50 of 7 nM ). |
| Author | Ahn, Soon Kil Nam, Ky-Youb Hong, Sung Pyo Choi, Nam Song Lee, Younho |
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| Cites_doi | 10.1016/j.bmcl.2011.06.097 10.1158/1535-7163.MCT-10-0799 10.1016/j.bmcl.2013.08.086 10.1016/j.bmc.2011.01.067 10.1038/nature09454 10.1016/j.pharmthera.2013.11.011 10.1021/jm300613w 10.1021/jm901081g 10.1021/jm501667n 10.1016/j.bmcl.2014.03.007 10.1016/j.canlet.2012.03.006 10.1016/j.cell.2009.12.040 10.1038/nrm3979 10.1016/j.bmcl.2012.04.015 10.1021/jm300016v 10.1016/j.yexmp.2013.10.005 |
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| Snippet | We describe the structure‐based design and synthesis of N‐(2,6‐difluorophenyl)‐3‐(9H‐purin‐6‐yl)pyridine‐2‐amine derivatives as a selective pan‐RAF kinase... We describe the structure‐based design and synthesis of N ‐(2,6‐difluorophenyl)‐3‐(9 H ‐purin‐6‐yl)pyridine‐2‐amine derivatives as a selective pan‐ RAF kinase... We describe the structure-based design and synthesis of N-(2,6-difluorophenyl)-3-(9H-purin-6-yl)pyridine-2-amine derivatives as a selective pan-RAF kinase... |
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| SubjectTerms | Anticancer Melanoma Pan-RAF inhibitor RAF Structure-based drug design 화학 |
| Title | Discovery of a Highly Specific and Potent Pan-RAF Inhibitor |
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