PF-03084014 is a reversible and selective inhibitor of γ-secretase with IC50 value of 6.2 nM . The Notch signaling pathway is triggered by the interaction of Notch ligand and Notch receptor located in the membrane of the adjacent cell. Then the NICD fragment is released through the cleavage caused by γ-secretase and subsequently regulates the transcription of the downstream genes. Since Notch signaling pathway appears to be important in the development of many cancers, the small-molecule inhibitors of γ-secretase are now developed as antitumor drugs in cancer treatment. PF-03084014 is one of these GSIs (γ-secretase inhibitors) that showed IC50 value of 6.2 nM in inhibiting the production of Aβ in HeLa cells. Meanwhile PF-03084014 has no significant inhibition effect on other receptors, proteases, ion channels and kinases, demonstrating its selectivity against γ-secretase [1, 2]. In CLL (chronic lymphocytic leukemia) cells from mutated CLL patients, the treatment of 10 μM PF-03084014 induced 29.63% apoptosis. PF-03084014 at concentration of 1 μM induced cell apoptosis with 7.84%. In Notch1-unmutated cells, PF-03084014 induced apoptosis with 22.04% and 4.44% at concentrations of 1 and 10 μM, respectively. PF-03084014 showed no significant apoptosis induction in normal T cells from Notch1-mutated CLL patients. In HPB-ALL cells harboring Notch1 mutations, PF-03084014 inhibited Notch receptor cleavage with IC50 value of 13.3 nM. It also down-regulated the expressions of Hes-1 and cMyc in the cells. It is found that PF-03084014 inhibits cell growth through induce cell cycle arrest at G0-G1 phase [1, 3]. In HPB-ALL tumor xenograft model, oral administration of PF-03084014 at dose of 50 mg/kg inhibited NICD production (70%-80%) after 24 hours. 150 mg/kg PF-03084014 caused maximal tumor growth inhibition of 92%. Besides that, the combination treatment of PF-03084014 and GEM significantly inhibited tumor growth and caused tumor regression in implanted PDA (pancreatic ductal adenocarcinoma) xenografts. It is also reported that the coadministration of PF-03084014 and dexamethasone can abrogate the gastrointestinal toxicity induced by PF-03084014 [1, 4].

Product information

CAS Number: 865773-15-5

Molecular Weight: 489.64

Formula: C27H41F2N5O

Chemical Name: 2-[(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]-N-(1-{1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl}-1H-imidazol-4-yl)pentanamide

Smiles: CC(C)(C)CNCC(C)(C)N1C=NC(=C1)NC(=O)C(CCC)NC1CC2C(CC1)=CC(F)=CC=2F

InChiKey: VFCRKLWBYMDAED-UHFFFAOYSA-N

InChi: 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)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

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