生物活性

Vismodegib is a potent hedgehog (Hh) signaling pathway inhibitor. Vismodegib is a potent inhibitor of two ABC transporters, ABCG2 and ABCB1/Mdr-1, with IC50 values of 1.4 and 3.0 µM, respectively. Vismodegib may have antitumor activity in locally advanced or metastatic basal-cell carcinoma.

The Gli-luc IC50 is 3nM.[2]

Based on murine10T1/2 (S12) embryonic fibroblast cells, the Gli-luc S12 IC50 is 13nM.[3]

体外研究

体内研究

0.5% methylcellulose+0.2% Tween 80

激酶实验

细胞实验

Survival curves[4]

HCC and H1339 cells were seeded in 25 cm2cell culture flasks and cultured for 24 h. Cells were exposed to GDC-0449 (25μM and 50μM) for 4 days and cell viability was evaluated by trypan blue exclusion cell counting. For cisplatin treatment, cells were 3 h exposed to 1μM cisplatin for 3 h followed by incubation with medium with Dimethylsulfoxide (detergent for GDC-0449, used as control) for 4 days. This approach was chosen because after application of cisplatin to humans a relevant plasma concentration of unbound cisplatin (active form) lasts for only 3 h (22).

动物实验

In vivo treatment of BALB/c mice with GDC-0449[5]

Groups of 6-to-8-week-old BALB/c female mice (5 mice per group) were subcutaneously inoculated in the right flank with 0.2 ml of suspension containing 1x106TUBO cells in phosphate-buffered saline (PBS) and treated per os with GDC-0449 (2 mg dissolved in 100μl of corn oil-ethanol in a 4:1 ratio, 3 times per week) or corn oil-ethanol (100μl in a 4:1 ratio, 3 times per week). The treatments were started simultaneously with the inoculation of TUBO cells.

A veterinary surgeon was present during the experiments. The animals care both before and after the experiments were performed only by trained personnel. Mice were bred under pathogen-free conditions.

Analysis of antitumor activity in vivo

Tumor growth was monitored weekly until tumor-bearing mice were sacrificed at the first signs of distress or when their tumors exceeded 20 mm in diameter. The tumors were measured with a caliper in two dimensions and the volumes were calculated by using the following formula: width2x length/2.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Zhang Y, Laterra J, Pomper MG. Hedgehog Pathway Inhibitor HhAntag691 Is a Potent Inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia. 2009;11(1):96-101.
[2] Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30(6):303-312.
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体内溶解度
约28 mg/mL

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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