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CAS No.: 935273-79-3

MK-4101 Catalog No. CSN18669

MK-4101 inhibits the hedgehog pathway with anti-tumor activity via the inhibition of proliferation and induction of apoptosis.

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靶点选择性

生物活性

实验方案

技术信息

生物活性

描述Persistent activation of hedgehod (Hh) pathway is involved in the pathogenesis of many cancers. Smoothened (Smo) is a G-protein-coupled receptor-like protein that functions as a key activator of Hh pathway. MK-4101 is a novel Smo antagonist that inhibits Hh signaling both in mouse Gli_Luc cell line and human KYSE180 esophageal cancer cells with IC50 values of 1.5μM and 1μM, respectively. It also inhibited the proliferation of medulloblastoma cells derived from Ptch1^−/+ mice with an IC50 value of 0.3μM. In the binding assay, MK-4101 only showed a 15-fold decrease of affinity for the resistant Smo mutated at position D477. In the mouse medulloblastoma allograft model, administration of MK-4101 for 3.5 weeks exhibited tumor regression (80 mg/kg, twice a day) and tumor growth inhibition (40 or 80mg/kg, once a day) compared to vehicle-treated controls. MK-4101 treatment (40 or 80mg/kg, once a day; 80mg/kg, twice a day) for 24 hours also downregulated the mRNA expression of Gli1 in tumors explanted from mice in a dose-dependent manner. The treatment of medulloblastoma allograft mice with MK-4101 (80mg/kg, twice a day) for 35 days completely inhibited tumor growth and prevented tumor relapse during the 3-month monitor period^[2].
作用机制MK-4101 binds directly to Smo to inhibit its activity^[2].

动物研究

剂量

Mice: 40 mg/kg, 80 mg/kg^[1] (p.o.)

给药途径

p.o.

动物药代数据

Animal	Mice^[1]	Rats^[1]
Dose	1 mg/kg (i.v.) 2 mg/kg (p.o.)	0.5 mg/kg (i.v.) 1 mg/kg (p.o.)
Administration	i.v. p.o.	i.v. p.o.
F	97% (p.o.)	87% (p.o.)
V_d	2.5 L/kg	1.4 L/kg
T_1/2	2.9 h	5.9 h
T_max	1 h	1.5 h
CL_p	10 ml/min/kg	4 ml/min/kg
C_max	1.3 μM	1.2 μM
AUC	3.3 μM·h (p.o.)	7.4 μM·h (p.o.)

参考文献

[1] Filocamo G, Brunetti M, et al. MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma. Mol Cancer Ther. 2016 Jun;15(6):1177-89.
[2] Filocamo G, Brunetti M, Colaceci F, Sasso R, Tanori M, Pasquali E, Alfonsi R, Mancuso M, Saran A, Lahm A, Di Marcotullio L, Steinkühler C, Pazzaglia S. MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma. Mol Cancer Ther. 2016 Jun;15(6):1177-89.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.0265 mL
- 10.1323 mL
- 20.2646 mL
- 5 mM
- 0.4053 mL
- 2.0265 mL
- 4.0529 mL
- 10 mM
- 0.2026 mL
- 1.0132 mL
- 2.0265 mL

技术信息

CAS号

935273-79-3

储存条件

粉末: Inert atmosphere,Store in freezer, under -20°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C24H24F5N5O

运输

蓝冰

分子量

493.47

别名

溶解度

DMSO	46.0 mg/mL (93.2 mM) warming
Water	insoluble

动物实验配方

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