6ANL

Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b]pyridazine-based p38 MAP Kinase Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.

Kaieda, A.Takahashi, M.Takai, T.Goto, M.Miyazaki, T.Hori, Y.Unno, S.Kawamoto, T.Tanaka, T.Itono, S.Takagi, T.Hamada, T.Shirasaki, M.Okada, K.Snell, G.Bragstad, K.Sang, B.C.Uchikawa, O.Miwatashi, S.

(2018) Bioorg Med Chem 26: 647-660

  • DOI: https://doi.org/10.1016/j.bmc.2017.12.031
  • Primary Citation of Related Structures:  
    5WJJ, 6ANL

  • PubMed Abstract: 

    We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: akira.kaieda@takeda.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14365Homo sapiensMutation(s): 2 
Gene Names: MAPK14CSBPCSBP1CSBP2CSPB1MXI2SAPK2A
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens)
Explore Q16539 
Go to UniProtKB:  Q16539
PHAROS:  Q16539
GTEx:  ENSG00000112062 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16539
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
T75 (Subject of Investigation/LOI)
Query on T75

Download Ideal Coordinates CCD File 
B [auth A]TAK-715
C24 H21 N3 O S
HEKAIDKUDLCBRU-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
T75 BindingDB:  6ANL IC50: min: 7.1, max: 240 (nM) from 2 assay(s)
Binding MOAD:  6ANL IC50: 240 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.954α = 90
b = 69.703β = 90
c = 74.294γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 1.1: 2018-02-14
    Changes: Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references