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5XVA

Crystal Structure of PAK4 in complex with inhibitor CZH216

Summary for 5XVA
Entry DOI10.2210/pdb5xva/pdb
DescriptorSerine/threonine-protein kinase PAK 4, [6-chloranyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone, ETHANOL, ... (4 entities in total)
Functional Keywordsatp binding pocket, transferase
Biological sourceHomo sapiens (Human)
Cellular locationCytoplasm : O96013
Total number of polymer chains1
Total formula weight33668.57
Authors
Zhao, F.,Li, H. (deposition date: 2017-06-27, release date: 2018-02-07, Last modification date: 2024-11-06)
Primary citationHao, C.,Zhao, F.,Song, H.,Guo, J.,Li, X.,Jiang, X.,Huan, R.,Song, S.,Zhang, Q.,Wang, R.,Wang, K.,Pang, Y.,Liu, T.,Lu, T.,Huang, W.,Wang, J.,Lin, B.,He, Z.,Li, H.,Li, F.,Zhao, D.,Cheng, M.
Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors.
J. Med. Chem., 61:265-285, 2018
Cited by
PubMed 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.
PubMed: 29190083
DOI: 10.1021/acs.jmedchem.7b01342
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.847 Å)
Structure validation

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