PF-3084014 is a reversible, noncompetitive, and selective γ-secretase inhibitor with IC50 of 6.2 nM.
The IC50 of 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. 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].
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, 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 PF-03084014 is reversible[1]. In the 7-day repeat dose toxicokinetic (TK) and first 1-month combination repeat dose studies, treatment with Dexamethasone alone and Dexamethasone with PF-03084014 cause moderate to marked body weight loss (-10% to -27%) after 7 days treatment. In the second 1-month combination repeat dose study, a similar magnitude of body weight loss (-10% to 22%) occurs with repeat dosing on the first week or third week of treatment with 100 mg/kg PF-03084014 and 1 mg/kg Dexamethasone. When Dexamethasone is not coadministered with PF-03084014 on the second week of study, increases (4%) in body weight are noted, suggesting that the body weight loss is reversible[2].
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.
[2]. Aguirre SA, et al. Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats. Toxicol Pathol. 2014;42(2):422-34.