Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

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Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors
Title:
Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors
Journal Title:
Journal of Medicinal Chemistry
Publication Date:
30 November 2017
Citation:
Hao, C., Zhao, F., Song, H., Guo, J., Li, X., Jiang, X., … Cheng, M. (2017). Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors. Journal of Medicinal Chemistry, 61(1), 265–285. doi:10.1021/acs.jmedchem.7b01342
Abstract:
Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors’ selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.
License type:
Publisher Copyright
Funding Info:
We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and Dr. S. Fan at the Beijing Advanced Innovation Center for Structural Biology for their assistance in data collection. We gratefully acknowledge the financial support from the National Natural Science Foundation of China (Grant 81230077) and Program for Innovative Research Team of the Ministry of Education, and Program for Liaoning Innovative Research Team in University. H.S. is grateful to the Agency for Science, Technology and Research (A*STAR), for its financial support (JCO DP Grant: 1334k00085). H.L. is supported by the National Natural Science Foundation of China (Grant 31470720) and the Tsinghua University Initiative Scientific Research Program.
Description:
ISSN:
1520-4804
0022-2623
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