| Description | 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. |
| In vitro | 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]。 |
| In vivo | 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]。 |
| Cell experiments | K07074 cells were plated to 24-well plates at 10<sup>5</sup> 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) |
| Target activity | Notch1:1 nM |
| Synonyms | LY3039478 |
| molecular weight | 464.44 |
| Molecular formula | C22H23F3N4O4 |
| CAS | 1421438-81-4 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | DMSO: 55 mg/mL (118.42 mM) H2O: < 1 mg/mL (insoluble or slightly soluble) |
| References | 1. Eli Lilly Company. The 8th SCI-RSC Symposium on Proteinase Inhibitor Design. 2013. 2. Mark H. Bender, et al. Cancer Res, 2013, 73(8 Suppl):Abstract nr 1131. 3. Bhagat TD, et al. J Biol Chem. 2017, 292(3):837-846. 4. Mäemets-Allas K, et al. Biochem Biophys Res Commun. 2016 May 20;474(1):118-25. 5. Lu B, He Y, He J, et al. Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell–like Properties in Osteosarcoma[J]. Molecular Cancer Research. 2020, 18(1): 57-67. |
| Citations | 1. Lu B, He Y, He J, et al. Epigenetic profiling identifies LIF as a super-enhancer controlled regulator of stem cell-like properties in osteosarcoma. Molecular Cancer Research. 2020, 18(1): 57-67 |