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Discovery of a Highly Specific and Potent Pan‐ RAF Inhibitor
Author(s) -
Hong Sung Pyo,
Lee Younho,
Choi Nam Song,
Nam KyYoub,
Ahn Soon Kil
Publication year - 2016
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.10917
Subject(s) - chemistry , kinase , ic50 , enzyme , mutant , v600e , cell culture , sulfonamide , pyridine , mutation , furan , biochemistry , microbiology and biotechnology , stereochemistry , in vitro , biology , medicinal chemistry , genetics , gene , organic chemistry
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 ).