生物活性

• 靶点	ERK2 IC50:0.3nM

• 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 BRAF_V600E-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 BRAF_V600E-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 BRAF_V600E-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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

• 动物研究
  剂量	Nude Mice: 5 mg/kg - 150 mg/kg[2] (p.o.) Rat: 10 mg/kg[3] (p.o.), 1 mg/kg[3] (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[3] Rats[3] Dogs[3] Dose 1 mg/kg (i.v.) 10 mg/kg (p.o.) 1 mg/kg (i.v.) 10 mg/kg (p.o.) 1 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 91.6% (p.o.) 97.7% (p.o.) 33.8% (p.o.) Vd 0.56 L/kg (i.v.) 0.36 ± 0.06 L/kg (i.v.) 1.61 L/kg (i.v.) T1/2 1.04 h (i.v.) 2.06 h (p.o.) 2.52 ± 0.07 h (i.v.) 2.02 ± 0.17 h (p.o.) 1.21 h (i.v.) 1.29 h (p.o.) Tmax 0.5 h (p.o.) 0.75 ± 0.29 h (p.o.) 2.00 h (p.o.) CL 6.24 ml/min/kg (i.v.) 1.67 ± 0.25 ml/min/kg (i.v.) 15.5 ml/min/kg (i.v.) AUC0→∞ 2672 ng·h/ml (i.v.) 24460 ng·h/ml (p.o.) 10179 ± 1528 ng·h/ml (i.v.) 98421 ± 14005 ng·h/ml (p.o.) 1091 ng·h/ml (i.v.) 3687 ng·h/ml (p.o.) Cmax/C0 1918 ng/ml (i.v.) 7768 ng/ml (p.o.) 6644 ± 1812 ng/ml (i.v.) 15,026 ± 2098 ng/ml (p.o.) 1033 ng/ml (i.v.) 1442 ng/ml (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03155620	Advanced Malignant Solid Neopl... more >>asm Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma Childhood Langerhans Cell Histiocytosis Histiocytic Sarcoma Juvenile Xanthogranuloma Malignant Glioma Recurrent Central Nervous System Neoplasm Recurrent Childhood Ependymoma Recurrent Childhood Malignant Germ Cell Tumor Recurrent Childhood Medulloblastoma Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Childhood Rhabdomyosarcoma Recurrent Childhood Soft Tissue Sarcoma Recurrent Ewing Sarcoma Recurrent Glioma Recurrent Hepatoblastoma Recurrent Langerhans Cell Histiocytosis Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Recurrent Osteosarcoma Recurrent Peripheral Primitive Neuroectodermal Tumor Recurrent Rhabdoid Tumor Refractory Central Nervous System Neoplasm Refractory Childhood Malignant Germ Cell Tumor Refractory Ewing Sarcoma Refractory Glioma Refractory Hepatoblastoma Refractory Langerhans Cell Histiocytosis Refractory Malignant Solid Neoplasm Refractory Medulloblastoma Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Osteosarcoma Refractory Peripheral Primitive Neuroectodermal Tumor Refractory Rhabdoid Tumor Refractory Rhabdomyosarcoma Rhabdoid Tumor Stage III Osteosarcoma AJCC v7 Stage III Soft Tissue Sarcoma AJCC v7 Stage IV Osteosarcoma AJCC v7 Stage IV Soft Tissue Sarcoma AJCC v7 Stage IVA Osteosarcoma AJCC v7 Stage IVB Osteosarcoma AJCC v7 Wilms Tumor Collapse <<	Phase 2	Recruiting	September 30, 2027	-
  NCT02608229	Pancreatic Cancer ... more >> Cancer of Pancreas Cancer of the Pancreas Pancreas Cancer Collapse <<	Phase 1	Recruiting	May 31, 2022	United States, Missouri ... more >> Washington University School of Medicine Recruiting Saint Louis, Missouri, United States, 63110 Contact: Andrea Wang-Gillam, M.D., Ph.D.    314-362-5740    awang-gillam@wustl.edu    Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D.          Sub-Investigator: Manik Anin, M.D.          Sub-Investigator: Kian-Huat Lim, M.D., Ph.D.          Sub-Investigator: Kathryn Robinson, M.D.          Sub-Investigator: Caron Rigden, M.D.          Sub-Investigator: Preet Singh, M.D.          Sub-Investigator: Rama Suresh, M.D.          Sub-Investigator: Ben Tan, M.D.          Sub-Investigator: Ashiq Masood, M.D.          Sub-Investigator: Timothy Rearden, M.D.          Sub-Investigator: Anna Roshal, M.D.          Sub-Investigator: Olivia Aranha, M.D., Ph.D.          Sub-Investigator: Nikolaos Trikalinos, M.D. Collapse <<
  NCT03417739	Uveal Melanoma	Phase 2	Recruiting	August 31, 2025	United States, Massachusetts ... more >> Massachusetts General Hospital Not yet recruiting Boston, Massachusetts, United States, 02214 Contact: Ryan Joseph Sullivan, MD       rsullivan7@partners.org    Principal Investigator: Ryan Joseph Sullivan, MD          Dana Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02215 Contact: Jennifer A Maattala    617-632-3992    jennifera_maattala@dfci.harvard.edu    Principal Investigator: Elizabeth Buchbinder, MD Collapse <<

• 更多
• 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.