4DCE

Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.211 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history. 


Literature

Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.

Bryan, M.C., Whittington, D.A., Doherty, E.M., Falsey, J.R., Cheng, A.C., Emkey, R., Brake, R.L., Lewis, R.T.

(2012) J Med Chem 55: 1698-1705

  • DOI: https://doi.org/10.1021/jm201565s
  • Primary Citation of Related Structures:  
    4DCE

  • PubMed Abstract: 

    Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.

    • Organizational Affiliation: 

    Medicinal Chemistry Research Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALK tyrosine kinase receptor
A, B
333Homo sapiensMutation(s): 1 
Gene Names: ALK
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UM73 (Homo sapiens)
Explore Q9UM73 
Go to UniProtKB:  Q9UM73
PHAROS:  Q9UM73
GTEx:  ENSG00000171094 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UM73
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0JF
Query on 0JF
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		(3S)-N-(4-methylbenzyl)-1-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}piperidine-3-carboxamide
C27 H33 N5 O4
BAQAWVMHTOQJCI-FQEVSTJZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0JF PDBBind:  4DCE IC50: 174 (nM) from 1 assay(s)
Binding MOAD:  4DCE IC50: 174 (nM) from 1 assay(s)
BindingDB:  4DCE IC50: min: 174, max: 384 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.211 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.612α = 90
b = 104.819β = 90.15
c = 57.817γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
EPMRphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-08
    Type: Initial release
  • Version 1.1: 2012-05-09
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations
  • Version 1.4: 2024-04-03
    Changes: Refinement description