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PDBsum entry 3w1f
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Transferase/transferase inhibitor
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PDB id
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3w1f
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References listed in PDB file
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Key reference
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Title
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Indazole-Based potent and cell-Active mps1 kinase inhibitors: rational design from pan-Kinase inhibitor anthrapyrazolone (sp600125).
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Authors
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K.Kusakabe,
N.Ide,
Y.Daigo,
Y.Tachibana,
T.Itoh,
T.Yamamoto,
H.Hashizume,
Y.Hato,
K.Higashino,
Y.Okano,
Y.Sato,
M.Inoue,
M.Iguchi,
T.Kanazawa,
Y.Ishioka,
K.Dohi,
Y.Kido,
S.Sakamoto,
K.Yasuo,
M.Maeda,
M.Higaki,
K.Ueda,
H.Yoshizawa,
Y.Baba,
T.Shiota,
H.Murai,
Y.Nakamura.
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Ref.
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J Med Chem, 2013,
56,
4343-4356.
[DOI no: ]
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PubMed id
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Abstract
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Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle
assembly check point, and the maintenance of chromosomal instability. Mps1 is
highly expressed in cancer cells, and its expression levels correlate with the
histological grades of cancers. Thus, selective Mps1 inhibitors offer an
attractive opportunity for the development of novel cancer therapies. To design
novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4,
SP600125) and its crystal structure bound to JNK1. Our design efforts led to the
identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM.
Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c
with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of
structure-based design using the X-ray structure of 23d bound to Mps1 culminated
in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549
lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over
120 and 166 kinases, respectively.
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