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Purity: ≥98%
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 has an IC50 value of 6.2 nM in a cell-free assay for inhibiting γ-secretase/gamma secretase. In order to prevent Notch receptors from being activated by proteases, nizocapestat binds to GS. Patients with desmoid tumors were enrolled in a Phase 3 clinical trial. Nirogacestat (Ogsiveo) was approved in 2023 by FDA for treating Desmoid tumours.
| Targets |
γ-secretase (IC50 = 6.2 nM)
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| ln Vitro |
PF-03084014 inhibits the cleavage of the Notch receptor in cellular assays using HPB-ALL cells that carry mutations in the heterodimerization and PEST domains of Notch1 (IC50 = 13.3 nM). PF-03084014 inhibits the expression of the Notch target genes Hes-1 and cMyc in HPB-ALL cells, with IC50 values of less than 1 nM and 10 nM, respectively. With IC50s ranging from 30 to 100 nM, PF-03084014 induces cell cycle arrest and apoptosis in a subset of human T-ALL cell lines, including HPB-ALL, DND-41, TALL-1, and Sup-T1. (Source: ) PF-03084014 has been shown to decrease HUVEC proliferation at a 0.5 μM IC50 and to decrease lumen formation at a 50 nM IC50. With MX1 cells, PF-03084014 (1 μM) has no antiproliferative effect, but it 95% inhibits migration.[2]
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| ln Vivo |
PF-03084014 orally administered at a single dose of 200 mg/kg results in approximately ~80% of xenograft HPB-ALL tumors to have maximal NICD inhibition. In this mode, PF-03084014 exhibits strong antitumor activity, with a maximal tumor growth inhibition of approximately ~92% at a dose of 150 mg/kg. Additionally, there is a notable decrease in NICD/Notch1, tumor mitotic index (Ki67), and apoptosis (activated caspase-3) staining.[1] PF-03084014 (120 mg/kg) causes tumor-bearing mice with breast cancer HCC1599 tumors to undergo apoptosis, antiproliferation, decreased tumor cell self-renewal ability, impaired tumor vasculature, and decreased metastasis activity. In a variety of breast xenograft models with a TGI value of at least 50%, PF-03084014 treatment exhibits strong antitumor activity.[2]
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| Enzyme Assay |
Through PCR amplification using appropriately crafted oligonucleotides and the APP695 cDNA, 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 produced. Remainder 596 of APP695, or the P1 residue in relation to the β-secretase cleavage site, is the Met that functions as the translation start site. The bacterial expression vector pET2-21b has this DNA fragment inserted into it. The recombinant protein, C100Flag, is purified using Mono-Q column chromatography after being overproduced in Escherichia coli [strain BL21(DE3)]. C100Flag (1.7 μM) is incubated with cell membranes (0.5 mg/mL) in buffer B (50 mM Pipes, pH 7.0y 5mM MgCl2/5 mM CaCl2/150 mM KCl) at 37°C 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%) or is incubated at 37°C. RIPA (150 mM NaCl/1.0% NP-40/0.5% sodium deoxycholatey 0.1% SDS/50 mM Tris HCl, pH 8.0) is added and boiled for five minutes to stop the reactions. After centrifuging the samples, the supernatant solutions are tested using ECL to detect the presence of Aβ peptides. The products Aβ40 and Aβ42 that result from the processing of C100Flag by γ-secretase have a Met at their N terminus, which makes them M-Aβ40 and M-Aβ42, respectively. Similarly, 0.125 mg/mL of the supernatant solution from HeLa cell membranes extracted with CHAPSO (solubilized γ-secretase) is incubated with C100Flag (1.7 μM) in buffer B that contains 0.25% CHAPSO. This is followed by an ECL assay for M-Aβ40 and M-Aβ42.
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| Cell Assay |
Growth media supplemented with 10% fetal bovine serum is used to seed 10,000 cells/well in 96-well plates. PF-03084014 is serially diluted in DMSO, certain concentrations of the compound or suitable controls are added to each well, and the cells are incubated for seven days at 37°C (with a final DMSO content of 0.1%). The plates are incubated for two to four hours after the cells are treated with resazurin at a final concentration of 0.1 mg/mL. Emission at 590 nm, following excitation at 560 nm, is how fluorescent signals are measured.
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| Animal Protocol |
Mice: Female athymic mice (nu/nu, 6-8 weeks) are employed. Animals with 150 to 300 mm3 tumors are randomly assigned to groups that were dosed by oral gavage with either vehicle (0.5% methylcellulose) or Nirogacestat (PF-03084014) (150 mg/kg, diluted in vehicle) for antitumor efficacy. Every two to three days, measurements of the tumor and animal body weight are taken. Vernier calipers are used to measure and calculate tumor volume (mm3). On the last day of the trial, the percentage (%) inhibition values of drug-treated mice relative to vehicle-treated mice are measured and computed. Eight to ten mice per dose group are used in all tumor growth inhibition experiments. To ascertain the P value, the student's t test is employed.
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| References |
| Molecular Formula |
C27H41F2N5O
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| Molecular Weight |
489.64
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| Exact Mass |
489.33
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| Elemental Analysis |
C, 66.23; H, 8.44; F, 7.76; N, 14.30; O, 3.27
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| CAS # |
1290543-63-3
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| Related CAS # |
Nirogacestat dihydrobromide;1962925-29-6
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| Appearance |
Solid powder
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| SMILES |
CCC[C@@H](C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C)N[C@H]2CCC3=C(C2)C(=CC(=C3)F)F
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| InChi Key |
VFCRKLWBYMDAED-REWPJTCUSA-N
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| 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
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| Chemical Name |
(2S)-2-[[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino]-N-[1-[1-(2,2-dimethylpropylamino)-2-methylpropan-2-yl]imidazol-4-yl]pentanamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.11 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.11 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1.43 mg/mL (2.92 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: 5% DMSO+40% PEG 300+5%Tween80+ 50%ddH2O: 2.4mg/ml |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05949099 | Recruiting | Drug: Nirogacestat Procedure: Cryoablation |
Desmoid Tumor | Stanford University | August 15, 2023 | Phase 2 |
| NCT05348356 | Active Recruiting |
Drug: Nirogacestat | Ovarian Granulosa Cell Tumor Ovarian Cancer |
Medanta, The Medicity, India | August 30, 2022 | Phase 2 |
| NCT05879146 | Not yet recruiting | Drug: Nirogacestat | Tumor | M.D. Anderson Cancer Center | October 30, 2023 | Phase 2 |
| NCT05556798 | Recruiting | Drug: Nirogacestat Drug: Pomalidomide |
Multiple Myeloma | Memorial Sloan Kettering Cancer Center |
October 4, 2022 | Phase 1 |
| NCT03785964 | Active Recruiting |
Drug: Nirogacestat oral tablet Drug: Placebo Oral Tablet |
Aggressive Fibromatosis Desmoid Tumor |
SpringWorks Therapeutics, Inc. | April 17, 2019 | Phase 3 |
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