Crenigacestat (LY3039478) is an orally bioavailable Notch inhibitor with an IC50 of ~1 nM in most of the tumor cell lines tested. Crenigacestat effectively inhibits mutant Notch receptor activity. In a xenograft tumor model, Crenigacestat inhibited expression of Notch-regulated genes and N1ICD cleavage in the tumor microenvironment.

Notch1:1 nM

Crenigacestat是一种新型小分子化合物，作为Notch-1胞内领域（N1ICD）剪切的极其有效的抑制剂，在大多数测试的肿瘤细胞系中具有约1 nM的IC50值。Crenigacestat还强效抑制突变Notch受体活性[2]。使用γ-分泌酶抑制剂Crenigacestat显著抑制了2种CCRCC（透明细胞肾细胞癌）细胞系的生长，且此抑制作用呈浓度依赖性。Crenigacestat处理还导致Myc和Cyclin A1两个基因表达降低，这两个基因是NOTCH驱动的增殖性标志在小鼠及人类模型系统中的一部分。此外，Crenigacestat处理还导致CCRCC细胞G0/G1期细胞周期阻滞[3]。

在小鼠中，其口服生物可用性(%F)为65%，清除率(CL)为41 mL/min/kg，分布容积(VDss)为3.8 L/kg。在大鼠中，其口服生物可用性(%F)为65%，CL为98 mL/min/kg，VDss为4.9 L/kg。在狗中，其口服生物可用性(%F)为67%，CL为3.8 mL/min/kg，VDss为1.4 L/kg[1]。在异种移植肿瘤模型中，Crenigacestat抑制了N1ICD的切割和肿瘤微环境中Notch调控基因的表达。Notch切割的抑制还导致了依赖Notch的异种移植模型中的凋亡诱导[2]。在用769-P CCRCC细胞异种移植的免疫缺陷NSG小鼠中，Crenigacestat治疗显著增加了生存时间并延迟了肿瘤生长，在独立的小鼠队列中展示了其在CCRC中的体内有效性[3]。

K07074 cells were plated to 24-well plates at 10⁵ cell/well. Viability of cells was assessed in quadruplicates at indicated timepoints using the CellTiter-Glo luminescent cell viability assay. To study the effect of the small molecular compounds on K07074 cell growth the compounds or DMSO were added to the growth media 24 h after seeding. The cells were incubated with inhibitors and DMSO as indicated. Cell viability was assessed as described above. Each experiment was carried out in triplicate and at least 3 independent experiments were performed. (Only for Reference)