Nirogacestat-PF-3084014-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemENirogacestatCat. No.: HY-15185CAS No.: 1290543-63-3Synonyms: PF-3084014; PF-03084014分式: CHFNO分量: 489.64作靶点: -secretase作通路: Neuronal Signaling; Stem Cell/Wnt储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解

2、性数据体外实验 DMSO : 50 mg/mL (102.12 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.11 mM); Suspended solution; Need ultrasonic and warming2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)1/3 Master of Small Molecules 您边的抑制剂师www.MedChemESolubility: 2.5 mg/mL (5.11 mM); Suspended solut

3、ion; Need ultrasonic3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.11 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Nirogacestat (PF-3084014)种可逆的竞争性的选择性的 -secretase 抑制剂，IC50 为 6.2 nM。IC50 & Target IC50: 6.2 nM (-secretase) 1体外研究 The IC50 of Nirogacestat (PF-03084014) for -secretase enzyme i

4、nhibition in cell-free assay for Aproduction using detergent solubilized membranes derived from HeLa cells is determined to be 6.2 nM.When tested for inhibition of Notch receptor cleavage in cellular assays using HPB-ALL cells that harbormutations in both the heterodimerization and PEST domains in N

5、otch1, the cell IC50 is determined to be 13.3nM. Nirogacestat (PF-03084014) causes a significant increase in caspase-3 activities in HPB-ALL and TALL-1 cells as well as an induction of cleaved PARP and cleaved caspase-3 after a 7-day treatment 1.体内研究 Nirogacestat (PF-03084014) shows robust antitumor

6、 activity in this model on 14-day twice daily dosing.Tumor growth inhibition is dose dependent, with maximal tumor growth inhibition of 92% obtained at highdose levels (150 mg/kg). In tumor growth inhibition studies where mice receive repetitive twice daily dosingfor more than a week, Nirogacestat (

7、PF-03084014) is well tolerated at dose levels below 100 mg/kg as nosignificant weight loss, morbidity, or mortality is observed. When the dose is increased to 150 mg/kg,however, mice have diarrhea and show weight loss (10-15%) approximately 10 days after compoundadministration. The body weight of tr

8、eated animals usually returns to normal if dosing holidays are given,suggesting that the toxicity of Nirogacestat (PF-03084014) is reversible 1. In the 7-day repeat dosetoxicokinetic (TK) and first 1-month combination repeat dose studies, treatment with Dexamethasone aloneand Dexamethasone with Niro

9、gacestat (PF-03084014) cause moderate to marked body weight loss (-10% to-27%) after 7 days treatment. In the second 1-month combination repeat dose study, a similar magnitude ofbody weight loss (-10% to 22%) occurs with repeat dosing on the first week or third week of treatment with100 mg/kg Niroga

10、cestat (PF-03084014) and 1 mg/kg Dexamethasone. When Dexamethasone is notcoadministered with Nirogacestat (PF-03084014) on the second week of study, increases (4%) in bodyweight are noted, suggesting that the body weight loss is reversible 2.PROTOCOLCell Assay 1 Cells are seeded in 96-well plates at

11、 2,000 (Sup-T1, Jurkat, and DND-41) or 10,000 (HPB-ALL or TALL-1)cells/well in growth media supplemented with 10% fetal bovine serum. Serial dilutions of Nirogacestat (PF-03084014) are done in DMSO, appropriate controls or designated concentrations of Nirogacestat (PF-03084014) are added to each wel

12、l, and cells are incubated at 37C for 7 days (final DMSO content 0.1%).Resazurin at a final concentration of 0.1 mg/mL is added to the cells and plates are incubated for 2 to 4hours. Fluorescent signals are read as emission at 590 nm after excitation at 560 nm. IC50 values arecalculated by using the

13、 sigmoidal dose-response (variable slope) in GraphPad Prism 1.2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEMCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 12 Athymic female mice (nu/nu, 6-8 weeks) are used. For antitumor

14、efficacy, animals bearing tumors of 150 to300 mm3 in size are randomly divided into groups that received either vehicle (0.5% methylcellulose) orNirogacestat (PF-03084014) (150 mg/kg, diluted in vehicle), and dosed by oral gavage. Animal body weightand tumor measurements are obtained every 2 to 3 da

15、ys. Tumor volume (mm3) is measured with Verniercalipers and calculated. Percent (%) inhibition values are measured on the final day of study for drug-treatedcompared with vehicle-treated mice and are calculated. For all tumor growth inhibition experiments, 8 to 10mice per dose group are used. Studen

16、ts t test is used to determine the P value.Rats 2Sprague-Dawley (SD) rats are useds. In the 7-day repeat dose TK study, 3 male rats per group are orallydosed with either 0.5% methylcellulose vehicle, Nirogacestat (PF-03084014) at 150 mg/kg/day, Nirogacestat(PF-03084014) at 150 mg/kg/day coadminister

17、ed with 1 of the oral Dexamethasone doses (0.25, 1.0, 2.5, or5.0 mg/kg/day) or Dexamethasone at 5 mg/kg/day and euthanized at 24 hr after the last dosing. The bloodcollection time points for determining Nirogacestat (PF-03084014) or Dexamethasone mean systemic plasmaconcentrations are 1, 2, 4, 7, an

18、d 24 hr post dosing. Test article-related findings are determined by assessingchanges in clinical signs, pre- and post-dose body weights. Blood samples for assessing systemic exposureof Nirogacestat (PF-03084014) and Dexamethasone are collected from all treatment groups at various timeson days 1 and

19、 7 of the study. Blood samples for hematology evaluation are also collected from all theanimals at 24 hr after the last dosing. The mean group changes in hematology parameters for treated ratsare expressed as a percentage change. Necropsy is performed 24 hr after the last dose, body weights arerecor

20、ded, and tissues are collected and submitted for histopathologic examinations.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 EMBO Mol Med. 2017 Jul;9(7):950-966. J Biol Chem. 2019 Jun 5. pii: jbc.RA119.008041. Int J Oncol. 2018 Jul;53(1):99-112. Mol Immunol. 2018 Jul;99:191-198.See more cust