Discovery of a Highly Specific and Potent Pan-RAF Inhibitor

• Published in: Bulletin of the Korean Chemical Society Vol. 37; no. 10; pp. 1632 - 1637
• Main Authors: Hong, Sung Pyo, Lee, Younho, Choi, Nam Song, Nam, Ky-Youb, Ahn, Soon Kil
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag GmbH & Co. KGaA 01.10.2016; Wiley‐VCH Verlag GmbH & Co. KGaA; 대한화학회
• Subjects: Anticancer; Melanoma; Pan-RAF inhibitor; RAF; Structure-based drug design; 화학
• ISSN: 1229-5949; 0253-2964; 1229-5949
• DOI: 10.1002/bkcs.10917

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).