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

Abstract

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^V600E 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-Raf^V600E (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 EGFR^T790M and PDGFR-β (IC₅₀: >10 μM). Despite having good potency for B-Raf and B-Raf^V600E in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf^600E. 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^V600E. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-Raf^V600E, and VEGFR2 kinases.

Keywords: 4-Anilinoquinazoline; EGFR; Kinase; Raf; VEGFR.