Nirogacestat dihydrobromide

Nirogacestat dihydrobromide (PF-3084014 dihydrobromide) is an orally active, reversible, and non-competitive selective γ-secretase inhibitor with an IC50 value of 6.2 nM. It exerts its effects by inhibiting the Notch signaling pathway while minimizing gastrointestinal toxicity, making it suitable for the study of Notch receptor-dependent tumors.

HPB-ALL:13.3 nmol/L, γ-secretase:6.2 nM

Method: Human T-ALL cell line HPB-ALL was treated with Nirogacestat dihydrobromide (0.001-10 μmol/L) for 72 h. NICD protein levels were detected by Western Blot, and Hes-1 and cMyc mRNA expression levels were measured by qRT-PCR.
Result: Nirogacestat dihydrobromide dose-dependently reduced NICD protein levels in HPB-ALL cells and significantly downregulated the expression of Notch target genes Hes-1 and cMyc [1].
Method: Human T-ALL cell lines HPB-ALL, DND-41, TALL-1, and Sup-T1 were treated with Nirogacestat dihydrobromide for 7 days. Cell proliferation inhibition was assessed by Resazurin fluorescence assay.
Result: Nirogacestat dihydrobromide inhibited the growth of multiple T-ALL cell lines [1].
Method: Human T-ALL cell line HPB-ALL was treated with Nirogacestat dihydrobromide (0.001-10 μmol/L) for 7 days. Cell cycle distribution was analyzed by flow cytometry (PI staining), and apoptosis was detected by Annexin V staining.
Result: Nirogacestat dihydrobromide induced G₀-G₁ cell cycle arrest in HPB-ALL cells and increased the proportion of sub-G₁ cells, inducing apoptosis [1].
Method: Human T-ALL cell lines HPB-ALL and TALL-1 were treated with Nirogacestat dihydrobromide (1 μmol/L) for 7 days. Caspase-3 activity was measured using a Caspase-3 activity assay kit, and cleaved PARP and cleaved caspase-3 protein levels were detected by Western Blot.
Result: Nirogacestat dihydrobromide significantly increased caspase-3 activity and induced the expression of cleaved PARP and cleaved caspase-3, indicating the induction of caspase-dependent apoptosis [1].

Method: Nude mice bearing HPB-ALL xenografts were orally administered a single dose of Nirogacestat dihydrobromide (50 mg/kg). Tumor tissues were collected at different time points (4, 8, and 24 h) post-administration, and NICD protein levels were detected by Western Blot.
Result: A >50% reduction in NICD was observed as early as 4 h after Nirogacestat dihydrobromide administration, and NICD inhibition reached 70%-80% at 24 h [1].
Method: Nude mice bearing HPB-ALL xenografts were orally administered Nirogacestat dihydrobromide (75 or 150 mg/kg, twice daily for 14 consecutive days). Tumor volume changes were measured using Vernier calipers.
Result: Nirogacestat dihydrobromide inhibited tumor growth in a dose-dependent manner, with a tumor growth inhibition rate of ~92% in the 150 mg/kg dose group [1].
Method: Nude mice bearing HPB-ALL xenografts were orally administered Nirogacestat dihydrobromide (150 mg/kg, twice daily for 7 consecutive days). Tumor tissues were collected for immunohistochemical staining to detect NICD, cleaved caspase-3, and Ki67 expression.
Result: Following Nirogacestat dihydrobromide treatment, perinuclear NICD staining in tumor tissues was reduced, cleaved caspase-3-positive cells were significantly increased, and Ki67-positive cells were decreased, indicating induction of apoptosis and inhibition of tumor cell proliferation [1].

DMSO: 64 mg/mL (98.24 mM), Sonication is recommended.