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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

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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Molecules 2018, 23(2), 417; https://doi.org/10.3390/molecules23020417
Received: 29 January 2018 / Revised: 8 February 2018 / Accepted: 11 February 2018 / Published: 14 February 2018
(This article belongs to the Section Medicinal Chemistry)
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. View Full-Text
Keywords: p21-activated kinase; PAK4 inhibitor; 2,4-diaminoquinazoline; anticancer p21-activated kinase; PAK4 inhibitor; 2,4-diaminoquinazoline; anticancer
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Wu, T.; Pang, Y.; Guo, J.; Yin, W.; Zhu, M.; Hao, C.; Wang, K.; Wang, J.; Zhao, D.; Cheng, M. 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. Molecules 2018, 23, 417.

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