产品说明书

Ulixertinib

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Chemical Structure| 869886-67-9 同义名 : BVD-523;VRT752271
CAS号 : 869886-67-9
货号 : A162263
分子式 : C21H22Cl2N4O2
纯度 : 99%+
分子量 : 433.331
MDL号 : MFCD22628898
存储条件：

粉末 Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(242.31 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 8 mg/mL clear

PO 0.5% CMC-Na 40 mg/mL suspension

生物活性
靶点

  • ERK2

    ERK2, IC50:<0.3 nM
描述 ERK1/2 (extracellular-signal-regulated kinases) is only known substrates of the MEK1/2 as well as the essential node in RAS/RAF/MEK/ERK signaling cascade, which can be activated by catalyzing the phosphorylation on T202/Y204 through MEK1/2. Ulixertinib is a selective ERK1/2 inhibitor with IC50 value <0.3nM for ERK2, and Ki value of 0.3nM/0.04nM for ERK1/2[1][2]. The cellular study showed that Ulixertinib can inhibited p-ERK/p-RSK (the ERK substrate) with IC50 values of 4.1/0.14μM, as well as cell proliferation with IC50 value of 0.18μM of A375 cells[1]. Treatment with Ulixertinib at concentration of 2μM for 24h caused decrease of the ERK substrate, p-RSK, and the transcription targeted by ERK1/2, DUSP6, in BRAFV600E-mutant A375 melanoma cells. Meanwhile the increased p-ERK1/2 levels by this ATP-competitive inhibitor can also be observed. Ulixertinib at 0.25-4μM for 24h caused G1-arrested concentration-dependently in BRAFV600E-mutant melanoma cell line, UACC-62. A cell-line–dependent increase in caspase-3/7 by Ulixertinib was observed, as 3-fold greater induction of caspase-3/7 in a subset of cell lines with sensitivity to Ulixertinib (IC50<2μM). This could be further confirmed by attenuated p-RB and Cyclin D1, as well as the increased apoptotic marker BIM-EL by Ulixertinib in cells. Oral administration with Ulixertinib at 50 and 100mg/kg twice daily for 2 weeks suppressed tumor growth in A375 xenografts. The suppression of Colo205 tumors by Ulixertinib for 18 days could be observed at dose of 100mg/kg. Combination therapy with BVD-523 at dose of 100mg/kg with BRAF inhibitor dabrafenib (50mg/kg) can produce produced a 100% regression and a maximum 100% tumor growth delay in an A375 BRAFV600E-mutant melanoma model[2].
作用机制 Ulixertinib is an ATP-competitive ERK1/2 inhibitor. Notice that measuring increased pERK1/2 levels could be considered as a pharmacodynamic biomarker for Ulixertinib, though inhibition of ERK1/2 targets such as pRSK or DUSP6 could still be observed.[2]
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human A375 cells Function assay 2 h Inhibition of ERK1/2 in human A375 cells harboring B-RAF V600E mutant assessed as decrease in phospho-RSK level after 2 hrs by Cellomics ArrayScanTM VTI imaging analysis, IC50=0.14 μM 25977981
human A375 cells Proliferation assay 72 h Antiproliferative activity against human A375 cells harboring B-RAF V600E mutant after 72 hrs by Cellomics ArrayScanTM VTI imaging analysis, IC50=0.18 μM 25977981
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.31mL

0.46mL

0.23mL

11.54mL

2.31mL

1.15mL

23.08mL

4.62mL

2.31mL
参考文献

[1]Ward RA, Colclough N, et al. Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2. J Med Chem. 2015 Jun 11;58(11):4790-801.

[2]Germann UA, Furey BF, et al. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363.

[3]Suresh PS, Jairam RK, et al. Prediction of Human Pharmacokinetics of Ulixertinib, a Novel ERK1/2 Inhibitor from Mice, Rats, and Dogs Pharmacokinetics. Eur J Drug Metab Pharmacokinet. 2018 Aug;43(4):453-460.