ACS Medicinal Chemistry Letters
Letter
Table 6. Antiproliferative Activity on HCT-116 Cells and STAT1 S727 Phosphorylation IC50 of Compounds 9, 12, and 19−21
HCT116 EC50 10%
HCT116 EC50 0.625%
MDCK perm AB
MDCK perm BA
STAT1 S727
phosphorylation IC50 (μM)
CDK8 IC50
(nM)
compd
FBS (μM)
FBS (μM)
× 10−6 cm/sec
× 10−6 cm/sec
9
4.4
>10
8.2
2.9
4.9
>10
7.7
4.3
5.4
3.9
3.9
4.0
7.0
>10
10.1
18.4
20.5
17.4
14.7
1.5
12
19
20
21
4.1
4.5
4.2
>10
>10
4.8
12.4
0.3
12.2
4.2
4.0
Koehler
6.7
18.2
17.2
0.0023
et al.10
flavopiridol
0.034
0.059
them with varying concentrations of 21. As can be seen in
Figure 6, each of these cell lines showed very similar growth
AUTHOR INFORMATION
■
Corresponding Author
4532.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank members of the DMPK and purification groups
within Genentech Small Molecule Drug Discovery for
purification and analytical support. The crystallographic
experiments were performed on the X06SA beamline at the
Swiss Light Source, Paul Scherrer Institut, Villigen, Switzerland.
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Selective and Orally Bioavailable Small-Molecule Modulators of the
inhibition curves, indicating that growth inhibition is likely not
a function of the inhibition of CDK8, but rather an off-target
effect.
Structure-guided modification of the well-known kinase
inhibitor Sorafenib led to a series of highly potent and selective
type II inhibitors of CDK8. Despite their lack of cellular
activity, we are confident that they are useful tool compounds
to investigate the biology of the CDK8 kinase domain.
Replacement of the phenyl ring linker by a saturated five-
membered ring improved potency, selectivity, and solubility.
Addition of a solubilizing group at the para position of the
phenyl urea greatly improved solubility and PPB while retaining
potency and selectivity. Similarly to what has been recently
reported,8 our series of type II inhibitors did not significantly
suppress phosphorylation of STAT1 at Ser727, while our series
of type I inhibitors showed strong activity.10
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
crystallographic experiment are deposited at the Protein Data
Bank with accession code: 5HVY.
Synthetic schemes describing the preparation of 1−32
are provided along with kinase selectivity and crystallo-
E
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX