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CAS No.: 1290543-63-3

Nirogacestat Catalog No. CSN17660

Synonyms: PF-3084014;PF-03084014

PF-3084014 is a reversible inhibitor of γ-secretase with IC50 of 6.2 nM.

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400-920-2911

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 γ secretase

IC50:6.2nM
描述PF-3084014 is a selective γ-secretase inhibitor with IC50 values of 6.2nM and 1.2nM for production of Aβ1-40 in cell-free enzyme assay and Aβ1-X in whole cells. The levels of Aβ were reduced dose-dependently in brain, cerebrospinal fluid, and plasma of young, plaque-free Tg2576 mice dosed acutely with PF-3084014 at doses ranging in 1-18 mg s.c. 3h post treatment, with more inhibition of Aβ1-40 compared with Aβ1-42. In addition to Aβ1-40 and Aβ1-42, dose-dependent reduction of Aβ1-34, Aβ1-37, and Aβ1-38 could also be observed in Tg2576 brain extracts after acute PF-3084014 treatment. PF-3084014 also exhibits inhibitory effect on Notch signaling with IC50 value of 13.3 nM in cellular assays using HPB-ALL cells that harbor mutations in both the heterodimerization and PEST domains in Notch1, without inhibitory effect on aspartic proteases (pepsin A, BACE 1, and cathepsin D) or serine proteases (chymotrypsin A, trypsin) up to 20μM. Dose-dependent decrease of Notch intracellular domain level could be observed in HPB-ALL cells treated with 0.001-10μM PF-3084014 for 3 days, accompanied with greatly decreased expression of target gene Hes-1 and cMyc. Consistent with the inhibition of Notch signaling, PF-03084014 led cell growth inhibition with IC50 values of 766nM and 170nM for HPB-ALL and T-ALL cells. The induction of a marked cell cycle arrest, decreased total Rb and increased P27 Kip1, as well as apoptosis shown by increased cleaved caspase-3 and PARP, could be observed in HPB-ALL cells post 7-day treatment of PF-3084014 at concentration ranging in 0.001-10μM. Intermittent administration of PF-03084014 orally at dose of 150mg/kg twice daily on cycle of 7-day on/7-day off for 15 days achieved efficacious tumor growth inhibition in HPB-ALL model with reduced gastrointestinal toxicity of PF-03084014 treatment which can also be reduced by Dexamethasone.
动物研究
剂量
Guinea pig: 0.003 mg/kg - 3 mg/kg^[1] (p.o.) Mice: 1 mg/kg - 32 mg/kg^[1] (s.c.), 150 mg/kg20530712 (p.o.)

给药途径
p.o., s.c.
临床研究

动物研究
剂量	Guinea pig: 0.003 mg/kg - 3 mg/kg^[1] (p.o.) Mice: 1 mg/kg - 32 mg/kg^[1] (s.c.), 150 mg/kg20530712 (p.o.)
给药途径	p.o., s.c.

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01981551	Desmoid Tumors ... more >> Aggressive Fibromatosis Collapse <<	Phase 2	Active, not recruiting	October 12, 2019	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<

参考文献

[1] Lanz TA, Wood KM, et al. Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther. 2010 Jul;334(1):269-77.
[2] Wei P, Walls M, et al. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010 Jun;9(6):1618-28.

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
- 2.0423 mL
- 10.2115 mL
- 20.4230 mL
- 5 mM
- 0.4085 mL
- 2.0423 mL
- 4.0846 mL
- 10 mM
- 0.2042 mL
- 1.0211 mL
- 2.0423 mL

技术信息

CAS号

1290543-63-3

储存条件

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

液体: -20°C:3-6 月 -80°C:12月

分子式

C27H41F2N5O

运输

蓝冰

分子量

489.64

别名

PF-3084014;PF-03084014

溶解度

DMSO	210.0 mg/mL (428.9 mM)
Water	insoluble

动物实验配方

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