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

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

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 de...

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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
id doaj-3d0076aed0404249919b4424bc10dd13
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spelling doaj-3d0076aed0404249919b4424bc10dd132020-11-25T01:58:24ZengMDPI AGMolecules1420-30492018-02-0123241710.3390/molecules23020417molecules23020417Discovery 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 ActivityTianxiao Wu0Yu Pang1Jing Guo2Wenbo Yin3Mingyue Zhu4Chenzhou Hao5Kai Wang6Jian Wang7Dongmei Zhao8Maosheng Cheng9Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaA 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.http://www.mdpi.com/1420-3049/23/2/417p21-activated kinasePAK4 inhibitor2,4-diaminoquinazolineanticancer
collection DOAJ
language English
format Article
sources DOAJ
author Tianxiao Wu
Yu Pang
Jing Guo
Wenbo Yin
Mingyue Zhu
Chenzhou Hao
Kai Wang
Jian Wang
Dongmei Zhao
Maosheng Cheng
spellingShingle Tianxiao Wu
Yu Pang
Jing Guo
Wenbo Yin
Mingyue Zhu
Chenzhou Hao
Kai Wang
Jian Wang
Dongmei Zhao
Maosheng Cheng
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
p21-activated kinase
PAK4 inhibitor
2,4-diaminoquinazoline
anticancer
author_facet Tianxiao Wu
Yu Pang
Jing Guo
Wenbo Yin
Mingyue Zhu
Chenzhou Hao
Kai Wang
Jian Wang
Dongmei Zhao
Maosheng Cheng
author_sort Tianxiao Wu
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2018-02-01
description 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.
topic p21-activated kinase
PAK4 inhibitor
2,4-diaminoquinazoline
anticancer
url http://www.mdpi.com/1420-3049/23/2/417
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