YO-01027

YO-01027 (Dibenzazepine;DBZ) is a potent γ-secretase inhibitor with IC₅₀ values of 2.92 and 2.64 nM for Notch and APPL cleavage, respectively. IC50 & Target: IC50: 2.92±0.22 (Notch), 2.64±0.30 (APPL) nM^[1] In Vitro: Increasing concentrations of DBZ administered to APPL- or Notch-expressing cells leads to the progressive accumulation of APPL CTF fragments and a decrease in NICD production in a strictly dose-dependent manner^[1]. The molecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the γ-secretase complex^[2]. In Vivo: DBZ blocks activated Notch1 signaling in abdominal aortic aneurysm (AAA) tissue from both Ang II-infused Apo E^-/- mice and human undergoing AAA repair. DBZ markedly prevents Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reverses Th2 response, in vivo^[3]. Administration of DBZ markedly attenuates renal fibrosis and expression of fibrotic markers, including collagen 1α1/3α1, fibronectin, and α-smoothmuscle actin. DBZ significantly inhibits ureteral obstruction -induced expression of transforming growth factor (TGF)- β, phosphorylated Smad 2, and Smad 3^[4].