Nirogacestat CAS# 1290543-63-3

Nirogacestat (PF-03084014) is a potent, selective, orally bioavailable γ-secretase inhibitor that blocks Notch receptor activation. In in vitro assays, Nirogacestat inhibits Notch signaling with an IC₅₀ of 2–5 nM in cell-based reporter systems and reduces the expression of Notch target genes such as HES1 and HEY1 in human cancer cell lines. It also suppresses proliferation of Notch-dependent tumor cells, including T-cell acute lymphoblastic leukemia (T-ALL) lines (IC₅₀ ≈ 10–30 nM). In in vivo studies, oral administration of Nirogacestat significantly inhibits tumor growth in multiple xenograft models, such as Notch-activated T-ALL and desmoid tumor models, with tumor growth inhibition (TGI) exceeding 80% at 100 mg/kg twice daily. In preclinical desmoid tumor models, sustained suppression of Notch signaling correlated with decreased β-catenin nuclear localization and reduced collagen deposition.