3WZJ

CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH 4-(6-(cyclohexylamino)-8-(((tetrahydro-2H-pyran-4-yl)methyl)amino)imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropylbenzamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.227 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.

Kusakabe, K.Ide, N.Daigo, Y.Itoh, T.Yamamoto, T.Hashizume, H.Nozu, K.Yoshida, H.Tadano, G.Tagashira, S.Higashino, K.Okano, Y.Sato, Y.Inoue, M.Iguchi, M.Kanazawa, T.Ishioka, Y.Dohi, K.Kido, Y.Sakamoto, S.Ando, S.Maeda, M.Higaki, M.Baba, Y.Nakamura, Y.

(2015) J Med Chem 58: 1760-1775

  • DOI: https://doi.org/10.1021/jm501599u
  • Primary Citation of Related Structures:  
    3WZJ, 3WZK

  • PubMed Abstract: 

    Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.


  • Organizational Affiliation

    Medicinal Research Laboratories, ‡Drug Developmental Research Laboratories, and §Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center , 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase TTK321Homo sapiensMutation(s): 0 
Gene Names: TTKMPS1MPS1L1
EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P33981 (Homo sapiens)
Explore P33981 
Go to UniProtKB:  P33981
PHAROS:  P33981
GTEx:  ENSG00000112742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33981
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
O43
Query on O43

Download Ideal Coordinates CCD File 
B [auth A]4-{6-(cyclohexylamino)-8-[(tetrahydro-2H-pyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide
C28 H36 N6 O2
ZOSFYOBMRYUXAN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
O43 BindingDB:  3WZJ IC50: min: 5.6, max: 6.6 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.227 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.961α = 90
b = 110.389β = 90
c = 114.356γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-11
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Refinement description
  • Version 1.2: 2022-08-24
    Changes: Database references, Derived calculations