YO-01027 (Dibenzazepine, DBZ) is a γ-secretase inhibitor, with the IC50 values of 2.64±0.30 and 2.92±0.22nM for APPL and Notch cleavage, respectively[1]. YO-01027 has the potential to modulate Notch-induced oncogenic events, inhibiting multiple tumor growth[2]. YO-01027 has been widely used as a model compound for the development of a range of multifunctional molecular probes targeting signal peptidases [3].
In vitro, YO-01027 treatment for 24h inhibited B16 cells, with an IC50 value of 300μM [4]. YO-01027 treatment for 48 hours significantly inhibited the viral replication in dengue virus (DENV)-infected Huh7.5.1 cells with an EC50 value of 20nM[5]. YO-01027 treatment at 0.2μM for 7 days significantly reduced cell viability and survival of ALL-SIL cells [6].
In vivo, YO-01027 treatment via intraperitoneal injection at a dose of 5µmol/kg/day for 14 days ameliorated liver steatosis in CoreTg mice and reduced expression of SREBP-1c without affecting body weight[7]. Intraperitoneal injection of YO-01027 (250μg/100g/day) for 8 days improved renal fibrosis in mice with unilateral ureteral ligation (UUO) injury, reduced collagen deposition and fibrosis marker expression in renal tissue[8].
References:
[1] Groth C, Alvord W G, Quinones O A, et al. Pharmacological analysis of Drosophila melanogaster γ-secretase with respect to differential proteolysis of Notch and APP[J]. Molecular pharmacology, 2010, 77(4): 567-574.
[2] Usui T, Sakurai M, Umata K, et al. Hedgehog signals mediate anti-cancer drug resistance in three-dimensional primary colorectal cancer organoid culture[J]. International journal of molecular sciences, 2018, 19(4): 1098.
[3] Fuwa H, Takahashi Y, Konno Y, et al. Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic γ-secretase inhibitors[J]. ACS chemical biology, 2007, 2(6): 408-418.
[4] Li Y, Zhang C, Nie Y, et al. Antitumor Activity of Ethyl Acetate Extraction of Wikstroemia chamaedaphne: Cell Cycle Arrest and Apoptosis-Inducing Activity in Melanoma Cells[J]. Records of Natural Products, 2022, 16(6): 571.
[5] Qiao W, Xie X, Shi P Y, et al. Druggable genome screens identify SPP as an antiviral host target for multiple flaviviruses[J]. Proceedings of the National Academy of Sciences, 2025, 122(8): e2421573122.
[6] Hounjet J, Habets R, Schaaf M B, et al. The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition[J]. Oncogene, 2019, 38(27): 5457-5468.
[7] Hirano J, Okamoto T, Sugiyama Y, et al. Characterization of SPP inhibitors suppressing propagation of HCV and protozoa[J]. Proceedings of the National Academy of Sciences, 2017, 114(50): E10782-E10791.
[8] Xiao Z, Zhang J, Peng X, et al. The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation[J]. The international journal of biochemistry & cell biology, 2014, 55: 65-71.
YO-01027 (Dibenzazepine, DBZ)是一种γ-分泌酶抑制剂，对APP裂解和Notch裂解的IC50值分别为2.64±0.30nM和2.92±0.22nM[1]。YO-01027具有调节Notch诱导的致癌事件、抑制多种肿瘤生长的潜力[2]。YO-01027已作为靶向信号肽酶的多功能分子探针开发的模型化合物[3]。
在体外，YO-01027处理24小时可抑制B16细胞活性，IC50值为300μM[4]。YO-01027处理登革病毒（DENV）感染的Huh7.5.1细胞48小时能显著抑制病毒复制，EC50值为20nM[5]。0.2μM的YO-01027处理ALL-SIL细胞7天可显著降低细胞活力和存活率[6]。
在体内，CoreTg小鼠每日腹腔注射YO-01027（5µmol/kg/day；持续14天）可改善肝脏脂肪变性并降低SREBP-1c表达，且不影响体重[7]。单侧输尿管结扎（UUO）损伤小鼠每日腹腔注射YO-01027（250μg/100g/day；持续8天）能改善肾纤维化，减少肾组织胶原沉积和纤维化标志物表达[8]。