MK0731

Names

[ Name ]:
MK0731

[Synonym ]:
(2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methyl-4-piperidinyl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide
1H-Pyrrole-1-carboxamide, 4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methyl-4-piperidinyl]-2,5-dihydro-2-(hydroxymethyl)-N-methyl-2-phenyl-, (2S)-
1H-Pyrrole-1-carboxamide,4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methyl-4-piperidinyl]-2,5-dihydro-2-(hydroxymethyl)-N-methyl-2-phenyl-,(2S)
ALR-3456,MK-0731
(S)-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
MK0731
MFCD11977272

Biological Activity

[Description]:

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].

[Related Catalog]:

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Kinesin

Signaling Pathways >> Cytoskeleton >> Kinesin

[Target]

KSP:2.2 nM (IC50)

[In Vitro]

MK-0731 (0.415-300 nM; 48 小时) 诱导 A2780 细胞凋亡，EC50 为 2.7 nM[1]。 MK-0731 对结合 hERG 通道的亲和力很小 (IC50=20.5 μM)[1]。 MK-0731 能够在细胞中诱导有丝分裂阻滞，IC50 为 19 nM[1]。 Apoptosis Analysis[1] Cell Line: A2780 cells Concentration: 0.415-300 nM Incubation Time: 48 h Result: Induced apoptosis with an EC50 of 2.7 nM.

[In Vivo]

MK-0731 (40 mg/kg/天; 皮下注射; 持续 11 天) 抑制高度过表达 Pgp 的 KB-v 肿瘤的生长，而紫杉醇 (HY-B0015) 没有作用[1]。 MK-0731 (2.5, 5, 10, 20, 40 mg/kg/天; 微型泵) 在 A2780 异种移植小鼠的肿瘤暴露和有丝分裂停滞方面表现出与剂量成比例的增加[1]。 MK-0731 (1 mg/kg/天; 静脉给药) 对于大鼠的 T1/2 为 1 小时，CL 为 66 mL/min•kg，Vss 3 L/kg[1]。 Pharmacokinetic Parameters of MK-0731[1]. rat iv (1 mg/kg) dog iv (0.4 mg/kg) rhesus iv (0.4 mg/kg) T1/2 (h) 1 2 1 CL (mL/min/kg) 66.7 15.1 23.1 Vss (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.

[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.

[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.

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
590.5±50.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₅H₂₈F₃N₃O₂

[ Molecular Weight ]:
459.504

[ Flash Point ]:
310.9±30.1 °C

[ Exact Mass ]:
459.213348

[ PSA ]:
47.02000

[ LogP ]:
3.61

[ Vapour Pressure ]:
0.0±1.7 mmHg at 25°C

[ Index of Refraction ]:
1.615