5USQ

ALK-5 kinase inhibitor complex

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors.

Sabat, M., Wang, H., Scorah, N., Lawson, J.D., Atienza, J., Kamran, R., Hixon, M.S., Dougan, D.R.

(2017) Bioorg Med Chem Lett 27: 1955-1961

  • DOI: https://doi.org/10.1016/j.bmcl.2017.03.026
  • Primary Citation of Related Structures:  
    5USQ

  • PubMed Abstract: 

    A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3-b]pyridine series with improved ADME properties.

    • Organizational Affiliation: 

    Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States. Electronic address: mark.sabat@takedasd.com.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TGF-beta receptor type-1299Homo sapiensMutation(s): 0 
Gene Names: TGFBR1, ALK5, SKR4
EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for P36897 (Homo sapiens)
Explore P36897 
Go to UniProtKB:  P36897
PHAROS:  P36897
GTEx:  ENSG00000106799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP36897
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8LY
Query on 8LY
Download Ideal Coordinates CCD File 
B [auth A]N-[2-(5-chloro-2-fluorophenyl)pyridin-4-yl]-2-[(piperidin-4-yl)methyl]-2H-pyrazolo[4,3-b]pyridin-7-amine
C23 H22 Cl F N6
QZJHLQYMHQMSIQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8LY BindingDB:  5USQ IC50: 100 (nM) from 1 assay(s)
EC50: 1000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.589α = 90
b = 78.33β = 90
c = 90.712γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-12
    Type: Initial release
  • Version 1.1: 2017-04-26
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Refinement description