{Reference Type}: Journal Article
{Title}: Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy.
{Author}: Hao C;Huang W;Li X;Guo J;Chen M;Yan Z;Wang K;Jiang X;Song S;Wang J;Zhao D;Li F;Cheng M;
{Journal}: Eur J Med Chem
{Volume}: 131
{Issue}: 0
{Year}: May 2017 5
{Factor}: 7.088
{DOI}: 10.1016/j.ejmech.2017.02.063
{Abstract}: Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 μM) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 μM). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4.