5F1Z

Structure of TYK2 with inhibitor 16: 3-azanyl-5-[(2~{S})-3-methylbutan-2-yl]-7-[1-methyl-5-(2-oxidanylpropan-2-yl)pyrazol-3-yl]-1~{H}-pyrazolo[4,3-c]pyridin-4-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.310 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.220 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.

Yogo, T.Nagamiya, H.Seto, M.Sasaki, S.Shih-Chung, H.Ohba, Y.Tokunaga, N.Lee, G.N.Rhim, C.Y.Yoon, C.H.Cho, S.Y.Skene, R.Yamamoto, S.Satou, Y.Kuno, M.Miyazaki, T.Nakagawa, H.Okabe, A.Marui, S.Aso, K.Yoshida, M.

(2016) J Med Chem 59: 733-749

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01857
  • Primary Citation of Related Structures:  
    5F1Z, 5F20

  • PubMed Abstract: 

    We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.


  • Organizational Affiliation

    Pharmaceutical Research Division, 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
Non-receptor tyrosine-protein kinase TYK2301Homo sapiensMutation(s): 0 
Gene Names: TYK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P29597 (Homo sapiens)
Explore P29597 
Go to UniProtKB:  P29597
PHAROS:  P29597
GTEx:  ENSG00000105397 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29597
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5U3
Query on 5U3

Download Ideal Coordinates CCD File 
B [auth A]3-azanyl-5-[(2~{S})-3-methylbutan-2-yl]-7-[1-methyl-5-(2-oxidanylpropan-2-yl)pyrazol-3-yl]-1~{H}-pyrazolo[4,3-c]pyridin-4-one
C18 H26 N6 O2
MUDVASGRHKWSTJ-JTQLQIEISA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.310 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.220 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.805α = 90
b = 47.805β = 90
c = 476.248γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-01-13 
  • Deposition Author(s): Skene, R.J.

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-13
    Type: Initial release
  • Version 1.1: 2016-01-20
    Changes: Database references
  • Version 1.2: 2016-02-10
    Changes: Database references
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Derived calculations