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]
Ulixertinib 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
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
搜索
