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PDBsum entry 3wzk
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PDB id:
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Transferase
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Title:
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Crystal structure of human mps1 catalytic domain in complex with n- cyclopropyl-4-(8-((thiophen-2-ylmethyl)amino)imidazo[1,2-a]pyrazin-3- yl)benzamide
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Structure:
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Dual specificity protein kinase ttk. Chain: a. Fragment: mps1 kinase domain, unp residues 516-820. Synonym: phosphotyrosine picked threonine-protein kinase, pyt. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ttk, mps1, mps1l1. Expressed in: cell-free synthesis
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Resolution:
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2.30Å
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R-factor:
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0.224
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R-free:
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0.280
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Authors:
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K.Kusakabe,N.Ide,Y.Daigo,T.Itoh,T.Yamamoto,E.Kojima,Y.Mitsuoka, G.Tadano,S.Tagashira,K.Higashino,Y.Okano,Y.Sato,M.Inoue,M.Iguchi, T.Kanazawa,Y.Ishioka,K.Dohi,Y.Kido,S.Sakamoto,S.Ando,M.Maeda, M.Higaki,H.Yoshizawa,H.Mura,Y.Nakamura
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Key ref:
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K.Kusakabe
et al.
(2015).
Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
J Med Chem,
58,
1760-1775.
PubMed id:
DOI:
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Date:
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29-Sep-14
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Release date:
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11-Feb-15
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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.
258 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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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
58:1760-1775
(2015)
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PubMed id:
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Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
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K.Kusakabe,
N.Ide,
Y.Daigo,
T.Itoh,
T.Yamamoto,
H.Hashizume,
K.Nozu,
H.Yoshida,
G.Tadano,
S.Tagashira,
K.Higashino,
Y.Okano,
Y.Sato,
M.Inoue,
M.Iguchi,
T.Kanazawa,
Y.Ishioka,
K.Dohi,
Y.Kido,
S.Sakamoto,
S.Ando,
M.Maeda,
M.Higaki,
Y.Baba,
Y.Nakamura.
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ABSTRACT
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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.
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