Nirogacestat

SKU: orb1300331

Description

Nirogacestat

Research Area

Cell Biology, Neuroscience, Protein Biochemistry, Stem Cell & Developmental Biology

Key Properties

• CAS Number: 1290543-63-3
• MW: 489.64
• Purity: 99.77%
• Formula: C₂₇H₄₁F₂N₅O
• SMILES: CCC[C@H](N[C@H]1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(cn1)C(C)(C)CNCC(C)(C)C
• Target: Apoptosis,Gamma-secretase
• Solubility: 10% DMSO+90% Corn Oil:3.3 mg/mL (6.74 mM);Ethanol:90 mg/mL (183.81 mM);H2O:< 1 mg/mL (insoluble or slightly soluble);DMSO:61.25 mg/mL (125.09 mM)

Bioactivity

• Target IC50:
  γ-secretase (cell-free assay):6.2 nM
• In Vivo:
  Nirogacestat(200 mg/kg, p.o.) causes maximal NICD inhibition for ～80% in xenograft HPB-ALL tumors. Nirogacestatshows robust antitumor activity in this mode with a maximal tumor growth inhibition of 92% at the dose of 150 mg/kg, accompanied by a significant reduction of NICD/Notch1, tumor mitotic index (Ki67), and apoptosis (activated caspase-3) staining. Nirogacestat(120 mg/kg) induces apoptosis, antiproliferation, reduces tumor cell self-renewal ability, impairs tumor vasculature, and decreases metastasis activity in breast cancer HCC1599 tumor-bearing mice. In various types of the breast xenograft models, Nirogacestathas significant antitumor activity (TGI>50%).
• In Vitro:
  Nirogacestatinhibits Notch receptor cleavage in HPB-ALL cells that harbor mutations in both the heterodimerization and PEST domains in Notch1 (IC50: 13.3 nM). Nirogacestatdownregulates Notch target genes Hes-1 (IC50<1 nM) and cMyc expression (IC50:10 nM) in HPB-ALL cells, respectively. Nirogacestatinhibits cell growth of a subset of human T-ALL cell lines (HPB-ALL, DND-41, TALL-1, and Sup-T1) through induction of cell cycle arrest and apoptosis (IC50s: 30-100 nM). Nirogacestatreduces proliferation of HUVECs (IC50: 0.5 μM) and decreases the lumen formation (IC50: 50 nM). Nirogacestat(1 μM) has no antiproliferative effect in MX1 cells; however, it inhibits migration by 95%.
• Cell Research:
  Cell lines: Human T-ALL cell lines HPB-ALL. Concentrations: ~1 μM. Method: Cells are seeded in 96-well plates at 10,000 cells/well in growth media supplemented with 10% fetal bovine serum.Serial dilutions of PF-03084014 are done in DMSO,appropriate controls or designated concentrations of PF-03084014 are added to each well,and cells are incubated at 37℃ 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.
• Animal Research:
  Animal Models: Human T-cell acute lymphoblastic leukemia xenografts HPB-ALL. Formulation: 0.5% methylcellulose. Dosages: 150 mg/kg,b.i.d. Administration: p.o.

Storage & Handling

• Storage: keep away from moisture,keep away from direct sunlight | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Apoptosis, cancer, Notch, inhibit, Nirogacestat, gastrointestinal, Inhibitor, Gamma secretase, Gammasecretase, PF 3084014, PF03084014, PF-03084014, PF-3084014, PF3084014, PF 03084014, toxicity, γ-secretase, γ secretase

Compound Identifiers

PubChem CID

46224413