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PDBsum entry 5ei6
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References listed in PDB file
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Key reference
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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 hybridization approach.
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Authors
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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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Ref.
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J Med Chem, 2016,
59,
3671-3688.
[DOI no: ]
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PubMed id
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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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