1290543-63-3 Usage
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.
Check Digit Verification of cas no
The CAS Registry Mumber 1290543-63-3 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,9,0,5,4 and 3 respectively; the second part has 2 digits, 6 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1290543-63:
(9*1)+(8*2)+(7*9)+(6*0)+(5*5)+(4*4)+(3*3)+(2*6)+(1*3)=153
153 % 10 = 3
So 1290543-63-3 is a valid CAS Registry Number.
1290543-63-3Relevant articles and documents
Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014
Brodney, Michael A.,Auperin, David D.,Becker, Stacey L.,Bronk, Brian S.,Brown, Tracy M.,Coffman, Karen J.,Finley, James E.,Hicks, Carol D.,Karmilowicz, Michael J.,Lanz, Thomas A.,Liston, Dane,Liu, Xingrong,Martin, Barbara-Anne,Nelson, Robert B.,Nolan, Charles E.,Oborski, Christine E.,Parker, Christine P.,Richter, Karl E.G.,Pozdnyakov, Nikolay,Sahagan, Barbara G.,Schachter, Joel B.,Sokolowski, Sharon A.,Tate, Barbara,Wood, Douglas E.,Wood, Kathleen M.,Van Deusen, Jeffrey W.,Zhang, Lei
, p. 2637 - 2640 (2011/06/20)
A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC50 lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
