2. Academic Validation
  3. Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor

Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor

  • Eur J Med Chem. 2016 Jun 30:116:239-251. doi: 10.1016/j.ejmech.2016.03.076.
Zhengsheng Zhan 1,  Xia Peng 2,  Qiufeng Liu 3,  Fang Chen 1,  Yinchun Ji 2,  Shanyan Yao 1,  Yong Xi 2,  Yipeng Lin 1,  Tiantian Chen 3,  Yechun Xu 4,  Jing Ai 5,  Meiyu Geng 6,  Wenhu Duan 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: ycxu@simm.ac.cn.
  • 5 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
  • 6 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
  • 7 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: whduan@simm.ac.cn.
PMID: 27061987 DOI: 10.1016/j.ejmech.2016.03.076
Abstract

c-Met/HGF overexpression has been detected in many human malignancies including tumors which are resistant to Anticancer therapy. Disrupting the aberrant c-Met/HGF axis has enjoyed significant progress in both preclinical and clinical antitumor campaign. To eliminate the OCH2-related metabolic deficiency of our previously reported triazolotriazine 2, we synthesized a series of CH2-/CF2-linked triazolotriazines and assessed their c-Met activities, leading to the highly potent compound 23 with IC50 values of 0.24 nM of enzymatic activity in c-Met and 0.85 nM of cellular activity in EBC-1 Cancer cell line, as well as with complete tumor regression in EBC-1 xenograft mice model at dose of 25 mg/kg via oral administration. Based on its potent anti-proliferative activities and favorable pharmacokinetic properties, 23 has been selected as a drug candidate for preclinical investigation.

Keywords

Antitumor; Kinase inhibitor; Triazolotriazines; c-Met.

Figures