生物活性

• 描述EW-7197 is a potent and selective ALK5/ALK4 with IC50 values of 13nM/17nM. It inhibited cellular ALK5 activity with IC50 values of 16.5nM and 12.1nM measured by a luciferase assay in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively^[6]. EW-7197 dose-dependently reduced TGFβ1-induced Smad3 phosphorylation at concentration>30nM in 4T1 cells post 30min, and blocked Smad2/3 nuclear translocation at 1μM. Also it inhibited TGFβ1-induced 4T1 cell migration and invasion as well as inhibited EMT in breast cancer cells. Administration of EW-7197 at doses of 0.625, 1.25, 2.5 and 5mg/kg dose-dependently prolonged the life span of BALB/c 4T1 mice via inhibition of EMT. It inhibited metastasis and enhanced the activity of cytotoxic T lymphocytes in 4T1 orthotopic–grafted mice at dose of 20mg/kg^[7].
• 作用机制The [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety of EW-7197 occupies the pocket for adenine ring of ATP and commonly forms a hydrogen bonding with NH of His283 in the backbone of hinge region of ALK5.^[6]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HEK293 cells	-	Function assay	-	Inhibition of human ERG channel expressed in HEK293 cells after 3 to 5.7 mins by whole-cell patch clamp technique, IC50=31.04 μM	24786585
  human HaCaT cells	-	Function assay	24 h	Inhibition of ALK5 in human HaCaT cells assessed as inhibition of TGFbeta1-induced luciferase activity after 24 hrs by luciferase reporter gene assay, IC50=0.0165 μM	24786585
  mouse 4T1 cells	-	Function assay	24 h	Inhibition of ALK5 in mouse 4T1 cells assessed as inhibition of TGFbeta1-induced luciferase activity after 24 hrs by luciferase reporter gene assay, IC50=0.0121 μM	24786585

• 动物研究
  剂量	Mice: 2.5 mg/kg[3] (p.o.); 40 mg/kg[2] (i.p.) Rat: 20 mg/kg[4] (p.o.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Mice[5] Dose 10 mg/kg Administration p.o. Cmax 625.0 ± 529.7 ng⁄ml T1/2 3.26 ± 2.47 h

• 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
  NCT02160106	Advanced Stage Solid Tumors	Phase 1	Active, not recruiting	October 2018	United States, North Carolina ... more >> Durham, North Carolina, United States, 27710 United States, Tennessee Nashville, Tennessee, United States, 37203 Nashville, Tennessee, United States, 37232 Collapse <<
  NCT03143985	Multiple Myeloma	Phase 1	Recruiting	January 2019	United States, Ohio ... more >> University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Recruiting Cleveland, Ohio, United States, 44106 Contact: Ehsan Malek, MD    216-844-0139    ehsan.malek@uhhospitals.org    Principal Investigator: Ehsan Malek, MD          Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Not yet recruiting Cleveland, Ohio, United States, 44195 Contact: Jason Valent, MD    216-445-7238    valentj3@ccf.org    Principal Investigator: Jason Valent, MD Collapse <<

• 参考文献

• [1] Jin CH, Krishnaiah M, et al. Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. J Med Chem. 2014 May 22;57(10):4213-38.

  [2] Son JY, Park SY, et al. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol Cancer Ther. 2014 Jul;13(7):1704-16.

  [3] Yoon JH, Jung SM, et al. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Mol Med. 2013 Nov;5(11):1720-39.

  [4] Jun EJ, Park JH, et al. EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus. Gastrointest Endosc. 2017 Jul;86(1):219-228.

  [5] Naka K, Ishihara K, et al. Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells. Cancer Sci. 2016 Feb;107(2):140-8.

  [6] Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Lee HJ, Park SJ, Park HJ, Lee K, Sheen YY, Kim DK. Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. J Med Chem. 2014 May 22;57(10):4213-38. doi: 10.1021/jm500115w. Epub 2014 May 13. PMID: 24786585.

  [7] Son JY, Park SY, Kim SJ, Lee SJ, Park SA, Kim MJ, Kim SW, Kim DK, Nam JS, Sheen YY. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol Cancer Ther. 2014 Jul;13(7):1704-16. doi: 10.1158/1535-7163.MCT-13-0903. Epub 2014 May 9. PMID: 24817629.

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