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Nirogacestat dihydrobromide

CAS No. : 1962925-29-6

MCE 站：Nirogacestat dihydrobromide

产品活性：Nirogacestat dihydrobromide (PF-3084014 dihydrobromide) 是一种有效的，具有口服活性的，可逆的非竞争性的选择性的 γ-secretase 抑制剂，IC₅₀ 为 6.2 nM。Nirogacestat dihydrobromide 抑制 Notch 信号通路，同时*小化胃肠道毒性。可用于研究 Notch 受体依赖性肿瘤。

研究领域：Neuronal Signaling  |  Stem Cell/Wnt  |  Apoptosis

作用靶点：γ-secretase  |  Apoptosis

In Vitro: The IC₅₀ of Nirogacestat (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. Nirogacestat 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.

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 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 is reversible.

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