5EOB

Crystal structure of CMET in complex with novel inhibitor

Summary for 5EOB

• Entry DOI: 10.2210/pdb5eob/pdb
• Descriptor: Hepatocyte growth factor receptor, 6-[bis(fluoranyl)-[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]methyl]quinoline (3 entities in total)
• Functional Keywords: cmet inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 1
• Total formula weight: 36425.93

Authors

Liu, Q.,Chen, T.,Xu, Y. (deposition date: 2015-11-10, release date: 2016-10-19, Last modification date: 2024-03-20)

Primary citation

Zhan, Z.,Peng, X.,Liu, Q.,Chen, F.,Ji, Y.,Yao, S.,Xi, Y.,Lin, Y.,Chen, T.,Xu, Y.,Ai, J.,Geng, M.,Duan, W.
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., 116:239-251, 2016

PubMed 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.

PubMed: 27061987
DOI: 10.1016/j.ejmech.2016.03.076

Experimental method

X-RAY DIFFRACTION (1.75 Å)