Indazole-Based
Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from
Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)
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Abstract
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
(<b>4</b>, SP600125) and its crystal structure bound to JNK1.
Our design efforts led to the identification of indazole-based lead <b>6</b> with an Mps1 IC<sub>50</sub> value of 498 nM. Optimization
of the 3- and 6-positions on the indazole core of <b>6</b> resulted
in <b>23c</b> with improved Mps1 activity (IC<sub>50</sub> =
3.06 nM). Finally, application of structure-based design using the
X-ray structure of <b>23d</b> bound to Mps1 culminated in the
discovery of <b>32a</b> and <b>32b</b> with improved potency
for cellular Mps1 and A549 lung cancer cells. Moreover, <b>32a</b> and <b>32b</b> exhibited reasonable selectivities over 120
and 166 kinases, respectively