1. Neuronal Signaling
    Stem Cell/Wnt
  2. γ-secretase
  3. Nirogacestat

Nirogacestat (Synonyms: PF-3084014; PF-03084014)

Cat. No.: HY-15185 Purity: 99.95%
Handling Instructions

Nirogacestat (PF-3084014) is a reversible, noncompetitive, and selective γ-secretase inhibitor with IC50 of 6.2 nM.

For research use only. We do not sell to patients.

Nirogacestat Chemical Structure

Nirogacestat Chemical Structure

CAS No. : 1290543-63-3

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10 mM * 1 mL in DMSO USD 99 In-stock
Estimated Time of Arrival: December 31
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10 mg USD 150 In-stock
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100 mg USD 1000 In-stock
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Customer Review

Based on 6 publication(s) in Google Scholar

Top Publications Citing Use of Products

    Nirogacestat purchased from MCE. Usage Cited in: EMBO Mol Med. 2017 Jul;9(7):950-966.

    Turnover of endogenous CD74 P8 is inhibited by RO4929079 and BMS-906024. Cell lysate Western blot of A20 cells treated with GSIs is developed with In-1 antibody. MK-0752 and Semagacestat tests used the same control lane (0 nM).

    Nirogacestat purchased from MCE. Usage Cited in: Int J Oncol. 2018 Jul;53(1):99-112.

    The expression of E-cadherin, N-cadherin and Snail in Enza-R cells is examined by western blot analysis. The cells are transfected with Ad-GFP or Ad-HepaCAM for 72 h and treated with 5 μM PF-3084014 for 48 h. GAPDH served as a loading control.
    • Biological Activity

    • Protocol

    • Purity & Documentation

    • References

    • Customer Review

    Description

    Nirogacestat (PF-3084014) is a reversible, noncompetitive, and selective γ-secretase inhibitor with IC50 of 6.2 nM.

    IC50 & Target

    IC50: 6.2 nM (γ-secretase)[1]

    In Vitro

    The IC50 of Nirogacestat (PF-03084014) for γ-secretase enzyme inhibition in cell-free assay for Aβ production 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 harbor mutations in both the heterodimerization and PEST domains in Notch1, the cell IC50 is determined to be 13.3 nM. 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].

    In Vivo

    Nirogacestat (PF-03084014) shows robust antitumor 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 high dose levels (150 mg/kg). In tumor growth inhibition studies where mice receive repetitive twice daily dosing for more than a week, Nirogacestat (PF-03084014) is well tolerated at dose levels below 100 mg/kg as no significant 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 compound administration. The body weight of treated 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 dose toxicokinetic (TK) and first 1-month combination repeat dose studies, treatment with Dexamethasone alone and Dexamethasone with Nirogacestat (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 of body weight loss (-10% to 22%) occurs with repeat dosing on the first week or third week of treatment with 100 mg/kg Nirogacestat (PF-03084014) and 1 mg/kg Dexamethasone. When Dexamethasone is not coadministered with Nirogacestat (PF-03084014) on the second week of study, increases (4%) in body weight are noted, suggesting that the body weight loss is reversible[2].

    Clinical Trial
    Molecular Weight

    489.64

    Formula

    C₂₇H₄₁F₂N₅O

    CAS No.

    1290543-63-3

    SMILES

    FC1=C2C(CC[[email protected]](N[[email protected]@H](CCC)C(NC3=CN(C(C)(C)CNCC(C)(C)C)C=N3)=O)C2)=CC(F)=C1

    Shipping

    Room temperature in continental US; may vary elsewhere

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Solvent & Solubility
    In Vitro: 

    DMSO : ≥ 50 mg/mL (102.12 mM)

    H2O : < 0.1 mg/mL (insoluble)

    *"≥" means soluble, but saturation unknown.

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 2.0423 mL 10.2116 mL 20.4232 mL
    5 mM 0.4085 mL 2.0423 mL 4.0846 mL
    10 mM 0.2042 mL 1.0212 mL 2.0423 mL
    *Please refer to the solubility information to select the appropriate solvent.
    In Vivo:
    • 1.

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% saline

      Solubility: 2.5 mg/mL (5.11 mM); Suspended solution; Need ultrasonic and warming

    • 2.

      Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in saline)

      Solubility: 2.5 mg/mL (5.11 mM); Suspended solution; Need ultrasonic

    • 3.

      Add each solvent one by one:  10% DMSO    90% corn oil

      Solubility: ≥ 2.5 mg/mL (5.11 mM); Clear solution

    *All of the co-solvents are provided by MCE.
    References
    Cell Assay
    [1]

    Cells are seeded in 96-well plates at 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 well, and cells are incubated at 37°C 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 4 hours. Fluorescent signals are read as emission at 590 nm after excitation at 560 nm. IC50 values are calculated by using the sigmoidal dose-response (variable slope) in GraphPad Prism[1].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1][2]

    Mice[1]
    Athymic female mice (nu/nu, 6-8 weeks) are used. For antitumor efficacy, animals bearing tumors of 150 to 300 mm3 in size are randomly divided into groups that received either vehicle (0.5% methylcellulose) or Nirogacestat (PF-03084014) (150 mg/kg, diluted in vehicle), and dosed by oral gavage. Animal body weight and tumor measurements are obtained every 2 to 3 days. Tumor volume (mm3) is measured with Vernier calipers and calculated. Percent (%) inhibition values are measured on the final day of study for drug-treated compared with vehicle-treated mice and are calculated. For all tumor growth inhibition experiments, 8 to 10 mice per dose group are used. Student's t test is used to determine the P value.
    Rats[2]
    Sprague-Dawley (SD) rats are useds. In the 7-day repeat dose TK study, 3 male rats per group are orally dosed with either 0.5% methylcellulose vehicle, Nirogacestat (PF-03084014) at 150 mg/kg/day, Nirogacestat (PF-03084014) at 150 mg/kg/day coadministered with 1 of the oral Dexamethasone doses (0.25, 1.0, 2.5, or 5.0 mg/kg/day) or Dexamethasone at 5 mg/kg/day and euthanized at 24 hr after the last dosing. The blood collection time points for determining Nirogacestat (PF-03084014) or Dexamethasone mean systemic plasma concentrations are 1, 2, 4, 7, and 24 hr post dosing. Test article-related findings are determined by assessing changes in clinical signs, pre- and post-dose body weights. Blood samples for assessing systemic exposure of Nirogacestat (PF-03084014) and Dexamethasone are collected from all treatment groups at various times on days 1 and 7 of the study. Blood samples for hematology evaluation are also collected from all the animals at 24 hr after the last dosing. The mean group changes in hematology parameters for treated rats are expressed as a percentage change. Necropsy is performed 24 hr after the last dose, body weights are recorded, and tissues are collected and submitted for histopathologic examinations.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References

    Purity: 99.95%

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    Product Name:
    Nirogacestat
    Cat. No.:
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