6EBW

hALK in complex with compound 9 (6-(((1S)-1-(5-Fluoropyridin-2-yl)ethyl)amino)-1-(3-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(morpholin-4-yl)methanone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.46 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.246 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of Potent, Selective, and Brain-Penetrant 1 H-Pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors.

Fushimi, M.Fujimori, I.Wakabayashi, T.Hasui, T.Kawakita, Y.Imamura, K.Kato, T.Murakami, M.Ishii, T.Kikko, Y.Kasahara, M.Nakatani, A.Hiura, Y.Miyamoto, M.Saikatendu, K.Zou, H.Lane, S.W.Lawson, J.D.Imoto, H.

(2019) J Med Chem 62: 4915-4935

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01630
  • Primary Citation of Related Structures:  
    6E0R, 6EBW, 6EDL

  • PubMed Abstract: 

    Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization of N-(2,4-difluorobenzyl)-3-(1 H-pyrazol-5-yl)imidazo[1,2- b]pyridazin-6-amine 1 guided by a cocrystal structure of compound 1 bound to ALK resulted in the identification of (6-(1-(5-fluoropyridin-2-yl)ethoxy)-1-(5-methyl-1 H-pyrazol-3-yl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)((2 S)-2-methylmorpholin-4-yl)methanone 13 as a highly potent, selective, and brain-penetrable compound. Intraperitoneal administration of compound 13 significantly decreased the phosphorylated-ALK (p-ALK) levels in the hippocampus and prefrontal cortex in the mouse brain. These results suggest that compound 13 could serve as a useful chemical probe to elucidate the mechanism of ALK-mediated brain functions and the therapeutic potential of ALK inhibition.


  • Organizational Affiliation

    Neuroscience Drug Discovery Unit, Research , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa , Kanagawa 251-8555 , Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALK tyrosine kinase receptor322Homo sapiensMutation(s): 0 
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
J3Y (Subject of Investigation/LOI)
Query on J3Y

Download Ideal Coordinates CCD File 
B [auth A][6-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}-1-(5-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl](morpholin-4-yl)methanone
C23 H24 F N7 O2
UYIANZRYPSGDFM-HNNXBMFYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
J3Y Binding MOAD:  6EBW IC50: 2.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.46 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.246 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.79α = 90
b = 57.336β = 90
c = 103.588γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-01
    Type: Initial release
  • Version 1.1: 2019-05-08
    Changes: Data collection, Database references
  • Version 1.2: 2019-05-15
    Changes: Data collection, Database references
  • Version 1.3: 2019-06-05
    Changes: Data collection, Database references
  • Version 1.4: 2024-03-13
    Changes: Data collection, Database references