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.
MK-0731 (0.415-300 nM; 48 h) induces apoptosis in A2780 cells with an EC50 of 2.7 nM[1]. MK-0731 displays little affinity for binding to the hERG channel (IC50=20.5 μM)[1]. MK-0731 has the ability to induce a mitotic block with an IC50 of 19 nM in cells[1].
MK-0731 (40 mg/kg/day; sc; for 11 days) inhibits the growth of KB-v tumors that highly overexpress Pgp, whereas Paclitaxel 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 T1/2 of 1 hours, a CL of 66 mL/min•kg, and a Vss of 3 L/kg for rats[1]. Pharmacokinetic Parameters of MK-0731 in rats[1].
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-metlpiperidin-4-yl]-2-(droxymetl)-N-metl-2-phenyl-2,5-didro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J Med Chem. 2008 Jul 24;51(14):4239-52.
[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.