5EI2

Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.239 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.

Innocenti, P.Woodward, H.L.Solanki, S.Naud, S.Westwood, I.M.Cronin, N.Hayes, A.Roberts, J.Henley, A.T.Baker, R.Faisal, A.Mak, G.W.Box, G.Valenti, M.De Haven Brandon, A.O'Fee, L.Saville, H.Schmitt, J.Matijssen, B.Burke, R.van Montfort, R.L.Raynaud, F.I.Eccles, S.A.Linardopoulos, S.Blagg, J.Hoelder, S.

(2016) J Med Chem 59: 3671-3688

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01811
  • Primary Citation of Related Structures:  
    5EH0, 5EHY, 5EI2, 5EI6, 5EI8

  • PubMed Abstract: 

    Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.


  • Organizational Affiliation

    Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase TTK313Homo 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
5O7
Query on 5O7

Download Ideal Coordinates CCD File 
B [auth A]~{N}-(2,4-dimethoxyphenyl)-8-(1-methylpyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine
C19 H18 N6 O2
YOEFXWPAQVJLHB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5O7 BindingDB:  5EI2 IC50: min: 46, max: 4840 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.239 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.64α = 90
b = 102.14β = 90
c = 109.99γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
xia2data reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-20
    Type: Initial release
  • Version 1.1: 2016-05-11
    Changes: Database references
  • Version 1.2: 2017-08-30
    Changes: Author supporting evidence
  • Version 1.3: 2018-04-04
    Changes: Data collection, Source and taxonomy