1 research outputs found
Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds
To develop RAF/VEGFR2 inhibitors that bind to the inactive
DFG-out conformation, we conducted structure-based drug design using
the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-<i>b</i>]pyridazine derivative. We designed various [5,6]-fused
bicyclic scaffolds (ring A, <b>1</b>–<b>6</b>)
possessing an anilide group that forms two hydrogen bond interactions
with Cys532. Stabilizing the planarity of this anilide and the nitrogen
atom on the six-membered ring of the scaffold was critical for enhancing
BRAF inhibition. The selected [1,3]thiazolo[5,4-<i>b</i>]pyridine derivative <b>6d</b> showed potent inhibitory activity
in both BRAF and VEGFR2. Solid dispersion formulation of <b>6d</b> (<b>6d-SD</b>) maximized its oral absorption in rats and showed
significant suppression of ERK1/2 phosphorylation in an A375 melanoma
xenograft model in rats by single administration. Tumor regression
(<i>T</i>/<i>C</i> = −7.0%) in twice-daily
repetitive studies at a dose of 50 mg/kg in rats confirmed that <b>6d</b> is a promising RAF/VEGFR2 inhibitor showing potent anticancer
activity