Design and synthesis of 4-anilinoquinazolines as Raf kinase inhibitors. Part 1. Selective B-Raf/B-RafV600E and potent EGFR/VEGFR2 inhibitory 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines

• Published in: Bioorganic chemistry 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: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2021
• Subjects: 4-Anilinoquinazoline; EGFR; Kinase; Raf; VEGFR; FDA; NSCLC; DMSO; Ras; NaAsc; VEGF; MAPK; dppf; H-bond; EGFR; PDB; MEK; TBAF; Kinase; Raf; CuAAC; IC50; VEGFR; PDGFR; 4-Anilinoquinazoline; DMF; GI50; TMSN3; ERK
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104715

Designed from combining the structural features of Raf inhibitory azastilbene 7 and EGFR/VEGFR inhibitory 4-anilinoquinazolines 1–3, 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazoline 9m exhibited potent and selective inhibitory activity toward B-Raf (IC50: 57 nM) and B-RafV600E (IC50: 51 nM) over C-Raf (IC50: 1.0 μM). Compound 9m also actively inhibited EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM) but not EGFRT790M and PDGFR-β (IC50 > 10 μM). [Display omitted] •4-Anilinoquinazoline 9m is a selective B-Raf/B-RafV600E kinase inhibitor.•The IC50 of 9m for B-Raf and B-RafV600E are 57 and 51 nM, respectively.•9m is less active for C-Raf with IC50 of 1.0 μM (~20 × selectivity).•9m potently inhibits EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM).•9m binds to the inactive conformations of B-Raf kinases. 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-RafV600E 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 (IC50: 57 nM) and B-RafV600E (IC50: 51 nM) over C-Raf (IC50: 1.0 μM). Compound 9m also actively inhibited EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM) but not EGFRT790M and PDGFR-β (IC50: >10 μM). Despite having good potency for B-Raf and B-RafV600E in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf600E. 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-RafV600E. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-RafV600E, and VEGFR2 kinases.