Cat. No.: HY-15185

Nirogacestat

(Synonyms: PF-3084014)

15 Cited Publications

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Based on 15 publication(s) in Google Scholar

Nirogacestat (PF-3084014) is a reversible, orally bioavailable, noncompetitive, and selective γ-secretase inhibitor with an IC₅₀ of 6.2 nM. Inhibition of Notch signaling by Nirogacestat while minimizing gastrointestinal toxicity presents a promising approach for research of Notch receptor-dependent cancers.

Nos produits utilisent uniquement pour la recherche. Nous ne vendons pas aux patients.

Pureté: 99.83%
CAS No.: 1290543-63-3
Formule: C₂₇H₄₁F₂N₅O
Masse moléculaire:489.64

Stockage:

Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 1 year , -20°C, 6 months

Nirogacestat Chemical Structure

CAS No.: 1290543-63-3

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Use of MCE Products

Fluorescent Dye

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Activité biologique
- Description
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- In Vivo
- Essai clinique
Chemical Information
Publications (15)
Solvant et solubilité
- In Vitro
- In Vivo
Protocole
Pureté et documentation
Références
Help & FAQs
Classifications
Bioz

Activité biologique

Description

IC₅₀ & Target

IC50: 6.2 nM (γ-secretase)^[1]

Cellular Effect

Cell Line	Type	Value	Description	References
H4	IC₅₀	1.2 nM Compound: 14f, PF-3084014	Inhibition of gamma-secretase in human H4 cells expressing APP Swedish mutant assessed as inhibition of amyloid beta (1 to 40) production by whole cell assay Inhibition of gamma-secretase in human H4 cells expressing APP Swedish mutant assessed as inhibition of amyloid beta (1 to 40) production by whole cell assay	[PMID: 21269827]
HeLa	IC₅₀	6.2 nM Compound: 11; PF-03084014	Inhibition of gamma secretase isolated from human HeLa cell derived P2 membrane assessed as reduction in amyloid beta (1 to 40 residues) using recombinant human APP-C100 as substrate by DELFIA-based immunoassay Inhibition of gamma secretase isolated from human HeLa cell derived P2 membrane assessed as reduction in amyloid beta (1 to 40 residues) using recombinant human APP-C100 as substrate by DELFIA-based immunoassay	[PMID: 27045975]

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].

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

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].

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

Essai clinique

NCT Number	Sponsor	Condition	Start Date	Phase A549
NCT01329991	Plexxikon\|		2011-05	PHASE1

Chemical Information

CAS No. 1290543-63-3
Appearance Solid
Masse moléculaire 489.64
Formule C₂₇H₄₁F₂N₅O
Color White to yellow
SMILES

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

PF-3084014
Livraison

Room temperature in continental US; may vary elsewhere.

Stockage

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	1 year
	-20°C	6 months

Publications (15)

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Journal Impact Factor

Nat Med

Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. [Abstract]

2023 Sep;29(9):2295-2306. PMID: 37653344

Nirogacestat purchased from MedChemExpress. Usage Cited in: Nat Med. 2023 Sep;29(9):2295-2306. [Abstract]

Soluble BCMA was measured from the supernatant of K562 cell line cultures using the sBCMA DuoSet kit. The cell lines were cultured with the γ-secretase inhibitor Nirogacestat (PF-3084014) (6.2 nM).
Cancer Cell

A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation. [Abstract]

2021 Mar 8;39(3):380-393.e8. PMID: 33689703

Nirogacestat purchased from MedChemExpress. Usage Cited in: Cancer Cell. 2021 Mar 8;39(3):380-393.e8. [Abstract]

Exposure to the gamma-secretase inhibitor Nirogacestat (PF308414) (6.2 nM), which targeted NOTCH signaling, led to decreased viability of mut-Ikzf3 CLL cells.
Nat Biotechnol

Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system. [Abstract]

2024 Nov 25. PMID: 39587229
Nat Mater

Blood-brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. [Abstract]

2025 Feb 17. PMID: 39962245
Neuron

Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. [Abstract]

2023 Jun 21;111(12):1898-1913.e5. PMID: 37040764

Nirogacestat purchased from MedChemExpress. Usage Cited in: Neuron. 2023 Jun 21;111(12):1898-1913.e5. [Abstract]

Treatment with γ-secretase inhibitor Nirogacestat (PF03084014) (1 mM) increased α-CTF to a level similar to ApoE CT treatment in HEK 293T cells.

Nirogacestat purchased from MedChemExpress. Usage Cited in: Neuron. 2023 Jun 21;111(12):1898-1913.e5. [Abstract]

Aβ40 production was measured from the incubation of purified β-CTF (0.1 mM) alone or co-incubation with γ-secretase (0.001 mM) after treatment with vehicle or Nirogacestat (PF03084014) (10 mM).
J Clin Invest

Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma. [Abstract]

2020 Feb 3;130(2):612-624. PMID: 31671073
EBioMedicine

Differential regulation of FADS2 by EZH2 reveals a metabolic vulnerability in ovarian cancer treatment. [Abstract]

2025 Aug 15:119:105879. PMID: 40818202
EMBO Mol Med

γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. [Abstract]

2017 Jul;9(7):950-966. PMID: 28539479

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

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).
ACS Appl Mater Interfaces

Magnetically Integrated Tumor-Vascular Interface System to Mimic Pro-angiogenic Endothelial Dysregulations for On-Chip Drug Testing. [Abstract]

2024 Sep 11;16(36):47075-47088. PMID: 39196896
Int J Oncol

HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro. [Abstract]

2018 Jul;53(1):99-112. PMID: 29658567

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

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.
J Biol Chem

PIM-induced phosphorylation of Notch3 promotes breast cancer tumorigenicity in a CSL-independent fashion. [Abstract]

2021 Jan-Jun:296:100593. PMID: 33775697
J Biol Chem

Individual and combined presenilin 1 and 2 knockouts reveal that both have highly overlapping functions in HEK293T cells. [Abstract]

2019 Jul 19;294(29):11276-11285. PMID: 31167792
Mol Immunol

Notch1 primes CD4 T cells for T helper type I differentiation through its early effects on miR-29. [Abstract]

2018 Jul:99:191-198. PMID: 29807327
bioRxiv

2025 May 28.
Research Square Print

2023 Mar 20.

Solvant et solubilité

In Vitro:

DMSO : 28.57 mg/mL (58.35 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

H₂O : < 0.1 mg/mL (insoluble)

View the Complete Stock Solution Preparation Table

Preparing Stock Solutions

View the Complete Stock Solution Preparation Table

Concentration Solvent Mass

1 mg

5 mg

10 mg

Concentration

Solvent

Mass

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. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.

Storage method and period of stock solution: -80°C, 1 year; -20°C, 6 months. When stored at -80°C, please use it within 1 year. When stored at -20°C, please use it within 6 months.

Calculateur de molarité

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

Concentration Concentration

Volume Volume

Molecular Weight Molecular Weight

Calculateur de dilution

Concentration _(start) × Volume _(start) = Concentration _(final) × Volume _(final)

Concentration _(start) Concentration _(start)

Volume _(start) Volume _(start)

Concentration _(final) Concentration _(final)

Volume _(final) Volume _(final)

In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

Stock Solution Working Solution

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

Protocol 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

This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.

Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

Protocol 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

This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.

Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

Protocol 3

Add each solvent one by one: 10% DMSO 90% Corn Oil

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

This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.

Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL Corn oil, and mix evenly.

Protocol 4

Add each solvent one by one: 5% DMSO 40% PEG300 5% Tween-80 50% Saline

Solubility: 1.43 mg/mL (2.92 mM); Suspended solution; Need ultrasonic

In Vivo Dissolution Calculator

Please enter the basic information of animal experiments:

Dosage Dosage
mg/kg
Animal Weight (Per Animal) Animal Weight (Per Animal)
g
Dosing Volume (Per Animal) Dosing Volume (Per Animal)
μL
Number of Animals Number of Animals

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.

Please enter your animal formula composition:

%
DMSO +

Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
%
+
+
%
Tween-80 + +
%
Saline +

The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).

Working solution concentration: 0.22 mg/mL

Protocole

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].

MedChemExpress (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.

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

Pureté et documentation

Select Batch:

Pureté: 99.98%

Assay: 99.98%

ee.: 99.98%

Fiche technique (278 KB)
SDS (393 KB)
- English - EN (393 KB)
- Français - FR (393 KB)
- Deutsch - DE (393 KB)
- Norwegian - NO (393 KB)
- Español - ES (393 KB)
- Swedish - SV (393 KB)
- Italian - IT (393 KB)
- Korean - KR (393 KB)
- Portuguese - PT (393 KB)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Instruction de manipulation (2659 KB)

Références

[1]. Wei P, et al. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010 Jun;9(6):1618-28. [Content Brief]

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

Complete Stock Solution Preparation Table

Storage method and period of stock solution: -80°C, 1 year; -20°C, 6 months. When stored at -80°C, please use it within 1 year. When stored at -20°C, please use it within 6 months.

Optional Solvent	Concentration Solvent Mass	1 mg	5 mg	10 mg	25 mg
DMSO	1 mM	2.0423 mL	10.2116 mL	20.4232 mL	51.0579 mL
	5 mM	0.4085 mL	2.0423 mL	4.0846 mL	10.2116 mL
	10 mM	0.2042 mL	1.0212 mL	2.0423 mL	5.1058 mL
	15 mM	0.1362 mL	0.6808 mL	1.3615 mL	3.4039 mL
	20 mM	0.1021 mL	0.5106 mL	1.0212 mL	2.5529 mL
	25 mM	0.0817 mL	0.4085 mL	0.8169 mL	2.0423 mL
	30 mM	0.0681 mL	0.3404 mL	0.6808 mL	1.7019 mL
	40 mM	0.0511 mL	0.2553 mL	0.5106 mL	1.2764 mL
	50 mM	0.0408 mL	0.2042 mL	0.4085 mL	1.0212 mL

Keywords

Nirogacestat

15 Cited Publications

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Nirogacestat

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Publications Citing Use of MedChemExpress (MCE) Nirogacestat

Activité biologique

Chemical Information

Publications (15)

Solvant et solubilité

Protocole

Pureté et documentation

Références

Help & FAQs

Complete Stock Solution Preparation Table

Nirogacestat Related Classifications

HY-15185 Related Classifications