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developed to discover selective PI4KIIIα inhibitors. After
a concise investigation, we have successfully identified
several classes of compounds showing a single-digit na-
nomolar value of IC50 against PI4KIIIα. They are com-
posed of different core structures, which could further
multiply the diversity after the successive tuning of the
accompanying substituents. We believe this method is
rational yet truly simple and this overall concept will also
be applicable to general kinase programs.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting information is available free of charge on the
ACS Publications website at DOI:
Synthetic procedures, experimental data, assay procedures
and PK profiles of 22 (PDF)
AUTHOR INFORMATION
Corresponding Author
* Phone: +81-72-681-9700. E-mail:makoto.shiozaki@jt.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Dr. Hiromasa Hashimoto for support.
ABBREVIATIONS
NS5A, Hepatitis C virus (HCV) nonstructural protein 5A;
PI3Kγ, Phosphoinositide 3-kinase gamma; PK, pharmacoki-
netics; LE, ligand efficiency.
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2) Hepatitis
(accessed by May 17, 2016).
C.
16) PI4KIIIβ homology model shown in Figure 2b is a ho-
mology model (with no ligand molecule). We observed
that when creating the PI4KIIIβ complex model with the
compound 5 in the same manner as the complex model
of PI4KIIIα, compound 5 was shifted to the opposite di-
rection from the affinity pocket, indicating that the
methoxymethyl moiety was too large for PI4KIIIβ.
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18) The corresponding arylbromide means as follows; SI-17
for 7, SI-23 for 8, SI-24 for 10, SI-25 for 11, and SI-22 for 12.
Please also see the supporting information.
19) The corresponding arylBipn means as follows; SI-27 for 9
and SI-30 for 14.
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20) SI-32 is the corresponding aryliodide for synthesis of 13 as
well as 16.
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