生物活性

• 描述The HGF/MET pathway plays an essential physiological role during embryogenesis, and a more restricted role in tissue regeneration and damage repair in healthy adults. In human cancer, the abnormal activation of the MET pathway is well documented. SAR125844 is a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK) with IC₅₀ values of 4.2, 0.22, 1.7, 6.5, 65 and 81 nM for wild-type MET, H1094Y, Y1235D, M1250T, L1195V and D1228H mutants, respectively. SAR125844 demonstrated a potent inhibition of MET phosphorylation with IC₅₀ values of 1.4, 3.9 and 5.1 nM in Hs 746T, SNU-5 and MKN-45 cell lines, respectively. In a panel of 31 tumor cell lines, SAR125844 inhibited cell proliferation in all cell lines with MET gene amplification, with IC₅₀ values in the nanomolar range (1-7 nM). SAR125844 (45 mg/kg) was able to completely inhibit MET kinase in 2 MET-amplified tumor models, with strong impact on downstream MAPK and PI3K pathways. Daily dosing in SNU-5 tumor bearing mice of SAR125844 at 45 mg/kg resulted in complete and almost complete tumor regression in 3/8 mice and 5/8 mice, respectively. SAR125844 (213 mg/kg) was able to maintain a long duration of MET inhibition up to 96h, and induce tumor regression in 2 MET-amplified gastric tumor models without any relevant impact on body weight^[3].
• 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
  NCT01657214	Neoplasm Malignant	Phase 1	Completed	-	Japan ... more >> Investigational Site Number 392001 Kashiwa-Shi, Japan Investigational Site Number 392004 Suita-Shi, Japan Investigational Site Number 392002 Sunto-Gun, Japan Investigational Site Number 392003 Takatsuki-Shi, Japan Korea, Republic of Investigational Site Number 410001 Seoul, Korea, Republic of, 110-744 Investigational Site Number 410004 Seoul, Korea, Republic of, 120-752 Investigational Site Number 410003 Seoul, Korea, Republic of, 135-710 Investigational Site Number 410002 Seoul, Korea, Republic of, 138-736 Collapse <<
  NCT02435121	Neoplasm Malignant	Phase 2	Completed	-	Belgium ... more >> Investigational Site Number 056001 Edegem, Belgium, B-2650 Collapse <<
  NCT01391533	Malignant Solid Tumors	Phase 1	Completed	-	United States, Massachusetts ... more >> Investigational Site Number 840001 Boston, Massachusetts, United States, 02114 France Investigational Site Number 250002 Dijon, France, 21079 Investigational Site Number 250001 Villejuif, France, 94805 Italy Investigational Site Number 380004 Bologna, Italy, 40138 Investigational Site Number 380002 Milano, Italy, 20133 Investigational Site Number 380001 Milano, Italy, 20141 Spain Investigational Site Number 724001 Barcelona, Spain, 08035 Investigational Site Number 724003 Madrid, Spain, 28040 Collapse <<

• 参考文献

• [1] Shitara K, Kim TM, et al. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer. Oncotarget. 2017 Jun 16.

  [2] Ugolini A, Kenigsberg M, et al. Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4] triazolo[4,3-b] pyridazin-3-ylsulfanyl] benzothiazo l-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844). J Med Chem. 2016 Aug 11;59(15):7066-74.

  [3] Egile C, Kenigsberg M, et al. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. Mol Cancer Ther. 2015 Feb;14(2):384-94