Design and synthesis of 4-anilinoquinazolines as Raf kinase inhibitors. Part 1. Selective B-Raf/B-Raf V600E and potent EGFR/VEGFR2 inhibitory 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines

• Published in: Bioorganic chemistry 2021-04, Vol.109, p.104715
• Main Authors: Lee, Cheng-I, Liao, Chu-Bin, Chen, Chih-Shang, Cheng, Fen-Ying, Chung, Yu-Hsuan, Wang, Yu-Chuan, Ciou, Sian-Yi, Hsueh, Wen-Yun, Lo, Tzu-Hao, Huang, Guan-Ru, Huang, Hsin-Yi, Tsai, Chia-Shen, Lu, Yu-Jung, Chuang, Shih-Hsien, Huang, Jiann-Jyh
• Format: Article
• Language: English
• ISSN: 1090-2120

This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-Raf and potent EGFR/VEGFR2 kinase inhibitors. Total 14 compounds of scaffold 9 having different side chains at the triazolyl group with/without fluoro substituents at the anilino group were synthesized and investigated. Among them, 9m with a 2-carbamoylethyl side chain and C-4'/C-6' difluoro substituents was the most potent, which selectively inhibited B-Raf (IC : 57 nM) and B-Raf (IC : 51 nM) over C-Raf (IC : 1.0 μM). Compound 9m also actively inhibited EGFR (IC : 73 nM) and VEGFR2 (IC : 7.0 nM) but not EGFR and PDGFR-β (IC : >10 μM). Despite having good potency for B-Raf and B-Raf in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf . The inferior activity of 9m for A375 was similar to that of sorafenib (6), suggesting that 9m might bind to the inactive conformations of B-Raf and B-Raf . Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-Raf , and VEGFR2 kinases.