生物活性

• 靶点

  B-Raf IC50:19nM

  B-Raf (V600E) IC50:8.2nM

  C-Raf IC50:56nM

  MEK1 IC50:160nM

• 描述The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. Among them, B-RAF is the most frequently mutated protein kinase in human cancers. Ro 5126766 is a unique and allosteric MEK/RAF signaling inhibitor with IC50 values of 8.2, 19, 56 and 160nM for BRAF^V600E mutant, BRAF, CRAF and MEK1 (measured by cell-free kinase assays), respectively. Treatment with Ro 5126766 at dose ranging in 0.01-10μM for 2h can reduce levels of both p-MEK and p-ERK dose-dependently till to undetectable levels in HCT116 KRAS-mutant colorectal cancer cells, whereas other MEK inhibitors PD0325901/GSK1120212 only inhibited ERK phosphorylation and either GDC-0879 or PLX-4720, the RAF inhibitor, induced p-MEK and p-ERK in response to paradoxical activation of RAF kinase as previous report. Consistent with the in vitro study, Ro 5126766 showed more effective inhibition on ERK signaling output than PD0325901 in chronically treated tumors with RAS mutations in the Calu-6 (NSCLC, KRAS Q61K) xenograft models. Oral administration of Ro 5126766 at dose of 1.5mg/kg, every day for 11 days showed more anti-tumor effect than PD0325901. Also Ro 5126766 at dose of 2mg/kg can cease the tumor growth on the PD0325901-refractory tumors in the HCT116 xenograft tumor model. Both of these more prolonged growth inhibition with Ro 5126766 was accompanied with suppression on both ERK signaling, p-MEK and p-ERK^[1].
• 作用机制The binding of Ro 5126766 caused MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF, thus resulting in formation of a stable MEK/RAF complex and inhibition of RAF kinase.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HCT116 cell	-	Function assay	96 h	Inhibition of human HCT116 cell growth after 96 hrs by counting kit-8 analysis, IC50=0.04 μM	24900832
  human A549 cells	10 μM	Function assay	1 h	Inhibition of MEK1 in human A549 cells assessed as reduction in pErk1/2 level at 10 uM after 1 hr by Western blotting analysis	25766633
  human C32 cells	-	Growth inhibition assay	-	Growth inhibition of human C32 cells harboring R-Raf V600E mutant, IC50=0.047 μM	24900832

• 更多

• 动物研究
  剂量	Mice: 0.1 mg/kg - 1 mg/kg[2] (p.o.)
  给药途径	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
  NCT00773526	Neoplasms	Phase 1	Completed	-	France ... more >> Villejuif, France, 94805 Spain Barcelona, Spain, 08003 United Kingdom Sutton, United Kingdom, SM2 5PT Collapse <<
  NCT03681483	Advanced Non-small Cell Lung C... more >>ancer Collapse <<	Phase 1	Recruiting	September 2019	United States, New Jersey ... more >> Memoral Sloan Kettering Basking Ridge Recruiting Basking Ridge, New Jersey, United States, 07920 Contact: Gregory Riely, MD, PhD    646-888-4199       Memoral Sloan Kettering Monmouth Recruiting Middletown, New Jersey, United States, 07748 Contact: Gregory Riely, MD, PhD    646-888-4199       United States, New York Memorial Sloan Kettering Commack Recruiting Commack, New York, United States, 11725 Contact: Gregory Riely, MD, PhD    646-888-4199       Memoral Sloan Kettering Westchester Recruiting Harrison, New York, United States, 10604 Contact: Gregory Riely, MD, PhD    646-888-4199       Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Gregory Riely, MD, PhD    646-888-4199       Contact: Charles Rudin, MD, PhD    646-888-4527       Principal Investigator: Gregory Riely, MD, PhD          Memorial Sloan Kettering Rockville Centre Recruiting Rockville Centre, New York, United States, 11570 Contact: Gregory Riely, MD, PhD    646-888-4199 Collapse <<
  NCT02407509	Solid Tumours ... more >> Multiple Myeloma Collapse <<	Phase 1	Recruiting	June 2021	United Kingdom ... more >> Royal Marsden NHS Foundation Trust Recruiting Sutton, Surrey, United Kingdom, SM2 5PT Contact: Udai Banerji, MBBS, PhD          Guy's and St Thomas' Hospital Not yet recruiting London, United Kingdom Contact: Alison Turner, PhD       alison.turner@icr.ac.uk    Contact: Joanna Dawes, PhD       DDU3808@icr.ac.uk Collapse <<

• 参考文献

• [1] Souers AJ, Leverson JD, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.