Discovery of 2-(4-Substituted-piperidin/piperazine-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-quinazoline-2,4-diamines as PAK4 Inhibitors with Potent A549 Cell Proliferation, Migration, and Invasion Inhibition Activity

• Main Authors: Tianxiao Wu, Yu Pang, Jing Guo, Wenbo Yin, Mingyue Zhu, Chenzhou Hao, Kai Wang, Jian Wang, Dongmei Zhao, Maosheng Cheng
• Format: Article
• Language: English
• Published: MDPI AG 2018-02-01
• Series: Molecules
• Subjects: p21-activated kinase; PAK4 inhibitor; 2,4-diaminoquinazoline; anticancer
• Online Access: http://www.mdpi.com/1420-3049/23/2/417
• ISSN: 1420-3049

A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.