Name: Nirogacestat (PF-03084014)
Brand: Selleck Chemicals
SKU: S8018
Availability: InStock
Rating: 5 (21 reviews)

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Quality Control

Batch: Purity: 99.31%

99.31

Related Targets	HDAC Caspase Proteasome MMP HCV Protease Cysteine Protease DPP Tyrosinase HIV Protease Serine Protease
Other Secretase Inhibitors	DAPT RO4929097 (RG-4733) LY411575 Dibenzazepine (YO-01027) Avagacestat (BMS-708163) MK-0752 Semagacestat (LY450139) MDL-28170 L-685,458 Itanapraced (CHF 5074)

Solubility

In vitro
Batch:

DMSO : 98 mg/mL (200.14 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 49 mg/mL

Water : Insoluble

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
Mass value Mass unit	Concentration value Concentration unit	Volume value Volume unit	Molecular weight (g/mol)

Dilution Calculator Molecular Weight Calculator

In vivo batch selection In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	2.400mg/ml (4.90mM)	Taking the 1 mL working solution as an example, add 50 μL of 48 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg

Average weight of animals: g

Dosing volume per animal: μL

Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO

%

% Tween 80

% ddH₂O

% DMSO

+

%

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Chemical Information, Storage & Stability

Molecular Weight	489.64	Formula	C₂₇H₄₁F₂N₅O	Storage (From the date of receipt)	3 years-20°Cpowder
CAS No.	1290543-63-3	Download SDF		Storage of Stock Solutions	1 year-80°Cin solvent 1 month-20°Cin solvent
Synonyms	PF-3084014			Smiles	CCCC(C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C)NC2CCC3=C(C2)C(=CC(=C3)F)F

Mechanism of Action

Targets/IC₅₀/Ki	gamma-secretase (cell-free assay) 6.2 nM
In vitro	Nirogacestat (PF-03084014) inhibits Notch receptor cleavage in cellular assays using HPB-ALL cells that harbor mutations in both the heterodimerization and PEST domains in Notch1 with IC50 of 13.3 nM. It downregulates Notch target genes Hes-1 and cMyc expression in HPB-ALL cells with IC50 of <1 nM and 10 nM, respectively, and 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. This compound reduces proliferation of HUVECs with IC50 of 0.5 μM, and decreases the lumen formation with an IC50 value of 50 nM. It (1 μM) has no antiproliferative effect in MX1 cells; however, it inhibits migration by 95%.
Kinase Assay	γ-secretase assay
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. This compound, Nirogacestat (PF-03084014), is used in the experimental context.
In vivo	Nirogacestat (PF-03084014) orally administrated in a single dose of 200 mg/kg causes maximal NICD inhibition for ∼80% in xenograft HPB-ALL tumors. It shows robust antitumor activity in this mode with a maximal tumor growth inhibition of ∼92% at a dose of 150 mg/kg, accompanied by a significant reduction of NICD/Notch1, tumor mitotic index (Ki67), and apoptosis (activated caspase-3) staining. At 120 mg/kg, this compound induces apoptosis, antiproliferation, reduces tumor cell self-renewal ability, impairs tumor vasculature, and decreases metastasis activity in breast cancer HCC1599 tumor-bearing mice. Its treatment displays significant antitumor activity in various types of the breast xenograft models with TGI value of at least 50%.
References	[1] https://pubmed.ncbi.nlm.nih.gov/20530712/ [2] https://pubmed.ncbi.nlm.nih.gov/22806875/ [3] https://pubmed.ncbi.nlm.nih.gov/10801983/

Applications

Methods	Biomarkers	Images	PMID
Western blot	N1ICD / Hes-1 / Hey-1 / p-MEK / MEK / c-PARP		23402814

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT02338531	Withdrawn	Breast Cancer	Jules Bordet Institute	June 2015	Phase 2
NCT02299635	Terminated	Triple Negative Breast Neoplasms	Pfizer	February 3 2015	Phase 2
NCT02109445	Terminated	Metastatic Cancer Pancreas	Pfizer\|Academic GI Cancer Consortium (AGICC)	September 3 2014	Phase 2
NCT01876251	Terminated	Breast Cancer Metastatic	Pfizer	November 4 2013	Phase 1

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Nirogacestat (PF-03084014) γ-Secretase inhibitor

Chemical Structure

Molecular Weight: 489.64