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PDBsum entry 5ei6
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PDB id:
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Transferase
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Title:
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Rapid discovery of pyrido[3,4-d]pyrimidine inhibitors of monopolar spindle kinase 1 (mps1) using a structure-based hydridization approach
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Structure:
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Dual specificity protein kinase ttk. Chain: a. Synonym: phosphotyrosine picked threonine-protein kinase,pyt. Engineered: yes. Other_details: n-(2,4-dimethoxyphenyl)-5-(1-methyl-1h-pyrazol-4-yl) isoquinolin-3-amine
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ttk, mps1, mps1l1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693
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Resolution:
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2.01Å
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R-factor:
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0.198
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R-free:
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0.221
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Authors:
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P.Innocenti,H.L.Woodward,S.Solanki,N.Naud,I.M.Westwood,N.Cronin, A.Hayes,J.Roberts,A.T.Henley,R.Baker,A.Faisal,G.Mak,G.Box,M.Valenti, A.De Haven Brandon,L.O'Fee,J.Saville,J.Schmitt,R.Burke,R.L.M.Van Montfort,F.I.Raymaud,S.A.Eccles,S.Linardopoulos,J.Blagg,S.Hoelder
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Key ref:
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P.Innocenti
et al.
(2016).
Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
J Med Chem,
59,
3671-3688.
PubMed id:
DOI:
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Date:
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29-Oct-15
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Release date:
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20-Apr-16
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PROCHECK
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Headers
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References
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P33981
(TTK_HUMAN) -
Dual specificity protein kinase TTK from Homo sapiens
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Seq:
Struc:
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857 a.a.
264 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.12.1
- dual-specificity kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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3.
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
59:3671-3688
(2016)
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PubMed id:
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Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
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P.Innocenti,
H.L.Woodward,
S.Solanki,
S.Naud,
I.M.Westwood,
N.Cronin,
A.Hayes,
J.Roberts,
A.T.Henley,
R.Baker,
A.Faisal,
G.W.Mak,
G.Box,
M.Valenti,
A.De Haven Brandon,
L.O'Fee,
H.Saville,
J.Schmitt,
B.Matijssen,
R.Burke,
R.L.van Montfort,
F.I.Raynaud,
S.A.Eccles,
S.Linardopoulos,
J.Blagg,
S.Hoelder.
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ABSTRACT
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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.
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Links
