3 research outputs found
Discovery of Imidazo[1,2‑<i>b</i>]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity
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-<i>a</i>]pyrazine <b>10a</b> was identified during an HTS
campaign. Although <b>10a</b> exhibited good biochemical activity,
its moderate cellular as well as antiproliferative activities needed
to be improved. The cocrystal structure of an analogue of <b>10a</b> guided our lead optimization to introduce substituents at the 6-position
of the scaffold, giving the 6-aryl substituted <b>21b</b> 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-<i>b</i>]pyridazine-based <b>27f</b>, an extremely potent (cellular Mps1 IC<sub>50</sub> =
0.70 nM, A549 IC<sub>50</sub> = 6.0 nM), selective Mps1 inhibitor
over 192 kinases, which could be orally administered and was active
in vivo. This <b>27f</b> demonstrated remarkable antiproliferative
activity in the nanomolar range against various tissue cancer cell
lines
Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)
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
Diaminopyridine-Based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation
Monopolar spindle 1 (Mps1) is an attractive cancer drug
target
due to the important role that it plays in centrosome duplication,
the spindle assembly checkpoint, and the maintenance of chromosomal
stability. A design based on JNK inhibitors with an aminopyridine
scaffold and subsequent modifications identified diaminopyridine <b>9</b> with an IC<sub>50</sub> of 37 nM. The X-ray structure of <b>9</b> revealed that the Cys604 carbonyl group of the hinge region
flips to form a hydrogen bond with the aniline NH group in <b>9</b>. Further optimization of <b>9</b> led to <b>12</b> with
improved cellular activity, suitable pharmacokinetic profiles, and
good in vivo efficacy in the mouse A549 xenograft model. Moreover, <b>12</b> displayed excellent selectivity over 95 kinases, indicating
the contribution of its unusual flipped-peptide conformation to its
selectivity