5XVA

Crystal Structure of PAK4 in complex with inhibitor CZH216


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

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

Hao, 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.

(2018) J Med Chem 61: 265-285

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01342
  • Primary Citation of Related Structures:  
    5XVA, 5XVF, 5XVG

  • 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.


  • Organizational Affiliation

    Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University , Shenyang 110016, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PAK 4293Homo sapiensMutation(s): 0 
Gene Names: PAK4KIAA1142
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O96013 (Homo sapiens)
Explore O96013 
Go to UniProtKB:  O96013
PHAROS:  O96013
GTEx:  ENSG00000130669 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96013
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Binding Affinity Annotations 
IDSourceBinding Affinity
8FU Binding MOAD:  5XVA Ki: 51 (nM) from 1 assay(s)
BindingDB:  5XVA Ki: 51 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.649α = 90
b = 64.699β = 90
c = 100γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Data collection, Database references, Refinement description