Table 4. Pharmacokinetic parameters of compound 1 in mouse (female) following IV and PO
Route
(dose)
Cmax
Tmax
h
T1/2
h
MRT
h
AUCextrap
ng*h/mL
AUC0-t
CL
Vdss
F
ng/mL
ng*h/mL
mL/kg/min
L/kg
%
IV
258
354
-
4.7
8.5
6.5
13
1007
4591
713
22.7
-
8.9
-
-
(1mpk)
Oral
4
3900
101
(5mpk)
Acknowledgments
The authors would like to acknowledge the assistance of Dr. Matt Marx in preparation of this
manuscript, Dr. Andy Jennings for providing the co-crystal figures and Sin-chi Matsumoto and
Nobuyuki Amano for MDR1 data.
References and notes
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a) Synthesis of compound 10: Nie, Z.; Feher, V.; Natala, S.; McBride, C.; Kiryanov, A.; Jones, B.; Lam, B.; Liu, Y.; Kaldor, S.; Stafford,
J.; Hikami, K.; Uchiyama, N.; Kawamoto, T.; Hikichi, Yu.; Matsumoto, S.; Amano, N.; Zhang, L.; Hosfield, D.; Skene, R.; Zou, H.; Cao,
X.; Ichikawa, T. Bioorg. Med. Chem. Lett. 2013, 23, 3662. b) Full experimental details for all compounds in this paper can be found in the
following patent application: WO2010025073.
10. PLK1 enzyme assay: The inhibitory activities of the inhibitors were assessed by the TR-FRET assay, which the ATP-dependent
phosphorylation of a biotinylated substrate peptide (1-μM) corresponding to residues 2470 through 2488 of mTOR protein (Biotin-
AGAGTVPESIHSFIGDGLV) is measured.
11. Cell proliferation assay: HT-29 human colon adenocarcinoma cells were seeded into 96-well plates at 3,000 cells/well in DMEM
(Dulbecco's Modified Eagle's Medium) plus 10% fetal calf serum (FCS). After 24 hours, cells were treated with serial dilutions of PLK1
inhibitors, and 72 hours later, the number of viable cells was assessed using the CellTiter-Glo Assay (Promega).
12. Hikichi, Y.; Honda, K.; Hikami, K.; Miyashita, H.; Kaieda, I.; Murai, S.; Uchiyama, N.; Hasegawa, M.; Kawamoto, T.; Sato, T.; Ichikawa,
13. The dissociation kinetics of PLK1 inhibitors was assessed by a method designed to determine the dissociation rate of a compound from an
enzyme. Inhibitors were mixed with PLK1 and incubated at room temperature for 60 min. to allow for sufficient binding. The
PLK1/inhibitor complex was then diluted into reaction buffer containing 1000-M ATP and 1-μM FAM-mTOR peptide, and this initiation