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

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0723
    CAS #: 1290543-63-3Purity ≥98%

    Description: Nirogacestat (formerly also known as PF-03084014; PF03084014; PF 3084014; PF-3084014) is an orally bioavailable, reversible, noncompetitive, and selective γ-secretase/gamma secretase (GS) inhibitor with potential anticancer activity. It inhibits γ-secretase/gamma secretase with an IC50 value of 6.2 nM in a cell-free assay. Nirogacestat acts by binding to GS, blocking the proteolytic activation of Notch receptors. It was in a in Phase 3 clinical trial for patients with desmoid tumors.

    References: Mol Cancer Ther. 2010 Jun;9(6):1618-28; Clin Cancer Res. 2012 Sep 15;18(18):5008-19. 

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    Molecular Weight (MW)489.64
    FormulaC27H41F2N5O
    CAS No.1290543-63-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 97 mg/mL (198.1 mM)          
    Water: <1 mg/mL
    Ethanol: 97 mg/mL (198.1 mM)          
    Other infoChemical Name: (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide
    InChi Key: VFCRKLWBYMDAED-REWPJTCUSA-N
    InChi Code: InChI=1S/C27H41F2N5O/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35)/t20-,23-/m0/s1
    SMILES Code: CCC[[email protected]](N[[email protected]@H]1CC2=C(C=C(F)C=C2F)CC1)C(NC3=CN(C(C)(C)CNCC(C)(C)C)C=N3)=O
    SynonymsPF 03084014; PF-3084014; Nirogacestat, PF03084014; PF-03084014; PF3084014; PF 3084014


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    In Vitro

    In vitro activity: PF-03084014 inhibits Notch receptor cleavage in cellular assays using HPB-ALL cells that harbor mutations in both the heterodimerization and PEST domains in Notch1with IC50 of 13.3 nM. PF-03084014 downregulates Notch target genes Hes-1, and cMyc expression in HPB-ALL cells with IC50 of<1 nM and 10 nM, respectively. PF-03084014 inhibits 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 with IC50s of 30-100 nM. PF-03084014 reduces proliferation of HUVECs with IC50 of 0.5 μM, and decreases the lumen formation with an IC50 value of 50 nM. PF-03084014 (1 μM) has no antiproliferative effect in MX1 cells; however, it inhibits migration by 95%.


    Kinase Assay: A DNA fragment encoding amino acids 596 - 695 of the 695-aa isoform of APP (APP695) and the Flag sequence (DYKDDDDK) at the C terminus is generated by PCR amplification with suitably designed oligonucleotides and the APP695 cDNA. The Met that serves as the translation start site is residue 596 of APP695 (the P1 residue with respect to theβ-secretase cleavage site). This DNA fragment is inserted into the prokaryotic expression vector pET2-21b. The recombinant protein, C100Flag, is overproduced in Escherichia coli [strain BL21(DE3)] and purified by Mono-Q column chromatography. C100Flag (1.7 μM) is incubated with cell membranes (0.5 mg/mL) in the presence of CHAPSO, CHAPS (3-[(3-cholamidopropyl)dim-ethylammonio]-1-propanesulfonate), or Triton X-100 (0, 0.125, 0.25, 0.5, or 1%) in buffer B (50 mM Pipes, pH 7.0y 5mM MgCl2/5 mM CaCl2/150 mM KCl) at 37°C. The reactions are stopped by adding RIPA (150 mM NaCl/1.0% NP-40/0.5% sodium deoxycholatey 0.1% SDS/50 mM Tris HCl, pH 8.0) and boiling for 5 min. The samples ae centrifuged and the supernatant solutions are assayed for the Aβ peptides by ECL. The Aβ40- and Aβ42-related products from γ-secretase-mediated processing of C100Flag possess a Met at the N terminus and are thus defined as M-Aβ40 and M-Aβ42, respectively. Likewise, supernatant solution (0.125 mg/mL) from CHAPSO-extracted HeLa cell membranes (solubilized γ-secretase) is incubated with C100Flag (1.7 μM) in buffer B containing 0.25% CHAPSO and subsequently assayed for M-Aβ40 and M-Aβ42 by using ECL. 


    Cell Assay: Cells (Human T-ALL cell lines HPB-ALL) 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.

    In VivoPF-03084014 orally administrated in a single dose of 200 mg/kg, causes maximal NICD inhibition for ∼80% in xenograft HPB-ALL tumors. PF-03084014 shows robust antitumor activity in this mode with a maximal tumor growth inhibition of ∼ 92% at dose of 150 mg/kg, accompanied by a significant reduction of NICD/Notch1, tumor mitotic index (Ki67), and apoptosis (activated caspase-3) staining. PF-03084014 (120 mg/kg) induces apoptosis, antiproliferation, reduces tumor cell self-renewal ability, impaires tumor vasculature, and decreases metastasis activity in breast cancer HCC1599 tumor-bearing mice. PF-03084014 treatment displays significant antitumor activity in various types of the breast xenograft models with TGI value of at least 50%.
    Animal modelHuman T-cell acute lymphoblastic leukemia xenografts HPB-ALL 
    Formulation & DosageDissolved in 0.5% methylcellulose; 150 mg/kg; Oral administration
    References

    Mol Cancer Ther. 2010 Jun;9(6):1618-28; Clin Cancer Res. 2012 Sep 15;18(18):5008-19. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

     

    PF-03084014 (PF-3084014)

    In vitro characterization of PF-03084014. A, inhibition of Notch signaling by PF-03084014 (100 nmol/L) blocks HUVEC-fibroblast lumen formation. Clin Cancer Res. 2012 Sep 15;18(18):5008-19.
     

    PF-03084014 (PF-3084014)

    Antitumor efficacy and pharmacodynamic assessment of PF-03084014 in the HCC1599 xenograft model. Clin Cancer Res. 2012 Sep 15;18(18):5008-19.
     

    PF-03084014 (PF-3084014)

    The antitumor and antimetastatic properties of PF-03084014 in the MX1 orthotopic model. Clin Cancer Res. 2012 Sep 15;18(18):5008-19.
     

    PF-03084014 (PF-3084014)

    The antitumor efficacy of PF-03084014 in breast cancer cells and xenograft models. Clin Cancer Res. 2012 Sep 15;18(18):5008-19.
     

    PF-03084014 (PF-3084014)

    Gene expression correlated with PF-03084014 sensitivity and treatment modulation. Clin Cancer Res. 2012 Sep 15;18(18):5008-19.


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