ALR-3456

Product NameALR-3456
CAS845256-65-7
MFC25H28F3N3O2
MW459.509
EINECS
MOL File845256-65-7.mol

Chemical Properties

Boiling point	590.5±50.0 °C(Predicted)
Density	1.32±0.1 g/cm3(Predicted)
pka	14.57±0.10(Predicted)
form	Solid
color	White to off-white

Usage And Synthesis

Uses

MK-0731 is a selective, non-competitive and allosteric kinesin spindle protein (KSP) inhibitor with an IC50 of 2.2 nM and a pKa of 7.6. MK-0731 is >20,000 fold selectivity against other kinesins. MK-0731 induces mitotic arrest and induces apoptosis in tumors. MK-0731 provides significant antitumor efficacy[1][2].

in vivo

MK-0731 (40 mg/kg/day; sc; for 11 days) inhibits the growth of KB-v tumors that highly overexpress Pgp, whereas Paclitaxel (HY-B0015) has no effect^[1].
MK-0731 (2.5, 5, 10, 20, and 40 mg/kg/day; minipump) exhibits a dose-proportional increase in both exposure and mitotic arrest in tumors in A2780-xenografted mice^[1].
MK-0731 (1 mg/kg/day; iv) has a T_1/2 of 1 hours, a CL of 66 mL/minkg, and a V_ss of 3 L/kg for rats^[1].
Pharmacokinetic Parameters of MK-0731 in rats^[1].

	rat iv (1 mg/kg)	dog iv (0.4 mg/kg)	rhesus iv (0.4 mg/kg)
T_1/2 (h)	1	2	1
CL (mL/min/kg)	66.7	15.1	23.1
V_ss (L/kg)	3.0	1.6	2.3

Animal Model:	Mice for the dual flank xenograft KB-3-1 and KB-v-1 cells^[1]
Dosage:	40 mpk
Administration:	SC; qd×1; for 11 days
Result:	Inhibited the growth of KB-v tumors that highly overexpress Pgp, whereas Paclitaxel (20 mpk; qd×5) had no effect.

IC 50

KSP: 2.2 nM (IC₅₀)

References

[1] Christopher D Cox, et al. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J Med Chem. 2008 Jul 24;51(14):4239-52. DOI:10.1021/jm800386y
[2] Kyle Holen, et al. A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors. Invest New Drugs. 2012 Jun;30(3):1088-95. DOI:10.1007/s10637-011-9653-1

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