A novel series of 4-(3-1 H -indazolyl)amino quinazoline derivatives were developed as PAK4 inhibitors based on a scaffold hopping strategy. Compounds 27e , 27g , 27i and 27j were found to exhibit potent inhibitory activity against PAK4 (IC 50 = 10, 13, 11 and 9 nM, respectively). Subsequent cellular assay demonstrated that compound 27e possessed the strongest antiproliferative activity against A549 cells with an IC 50 value of 0.61 μM, a little bit better than PF-3758309. Further anticancer mechanistic investigation revealed that compound 27e significantly induced apoptosis of A549 cells in a concentration-dependent manner and blocked the cell cycle at phase G0/G1. A docking model between compound 27e and PAK4 was proposed to elucidate its possible binding modes. As a promising PAK4 inhibitor, compound 27e may serve as a candidate for the development of novel PAK4-targeted anticancer drug.
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