| Identification | Back Directory | [Name]
PF-3084014 | [CAS]
1290543-63-3 | [Synonyms]
CS-2699
PF-3084014
Nirogacestat
PF-03084014 (PF-3084014)
PF-03084014 (Nirogacestat)
PF03084014;PF 03084014;PF-03084014
Nirogacestat(PF-03084014,PF-3084014)
(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
Pentanamide, 2-[[(2S)-6,8-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]amino]-N-[1-[2-[(2,2-dimethylpropyl)amino]-1,1-dimethylethyl]-1H-imidazol-4-yl]-, (2S)-
(S)-2-((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide Molecular Weight: 489.64 | [Molecular Formula]
C27H41F2N5O | [MDL Number]
MFCD19980705 | [MOL File]
1290543-63-3.mol | [Molecular Weight]
489.64 |
| Chemical Properties | Back Directory | [Boiling point ]
651.3±55.0 °C(Predicted) | [density ]
1.16±0.1 g/cm3(Predicted) | [storage temp. ]
room temp | [solubility ]
Water:1.0(Max Conc. mg/mL);2.04(Max Conc. mM) | [form ]
powder | [pka]
13.27±0.70(Predicted) | [color ]
white to beige | [Water Solubility ]
H2O: 1mg/mL, clear |
| Hazard Information | Back Directory | [Uses]
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[1]. | [Biochem/physiol Actions]
PF-03084014 inhibits the Notch signalling pathway. It contributes totumor suppression in breast, pancreatic carcinoma, hepatocellular carcinoma and progressive desmoid tumors. PF-03084014 in combination with dexamethasone elicits antileukemic effects in T-cell acute lymphoblastic leukemias (T-ALL). | [Enzyme inhibitor]
This novelγ-secretase inhibitor (FW = 489.66 g/mol; CAS 1290543-63-3; soluble in DMSO), also code-named HY-15185 and systematically named [(S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2- methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide], inhibitsγ-secretase reversibly, noncompetitively, and selectively, thereby reducing amyloid-b (Ab) production, with an in vitro IC50 of 1.2 nM in a whole-cell assay and 6.2 nM in cell-free assay. PF-03084014 inhibits Notch-related T- and B-cell maturation in an in vitro thymocyte assay with an EC50 of 2.1 μM. PF-3084014 had an IC50 on B- and T-cell reductions of 1.3 to 3 μM with a mean EC50 of 2.1 μM. This represents >300-fold separation from the broken-cell Aβ IC50 and >1500x separation from the whole-cell IC50. A single acute dose showed dose-dependent reduction in brain, cerebrospinal fluid (CSF), and plasma Ab . When dosed with PF- 3084014 for 5 days using an osmotic minipump (0.03 to 3 mg/kg/day), Guinea pigs exhibited dose-dependent Ab reduction in brain, CSF, and plasma. While otherγ-secretase inhibitors show high potency at elevating Ab in the conditioned media of whole cells and the plasma of multiple animal models and humans, such potentiation is not observed with PF- 3084014. By evoking antitumor and antimetastatic properties via pleiotropic mechanisms, experiments with PF-03084014 offer hope that Notch pathway downstream genes may be used to predict the antitumor activity of PF-03084014 in breast cancer patients. | [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]. | [References]
[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. DOI:10.1158/1535-7163.MCT-10-0034 |
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