Discovery of 6-benzyloxyquinolines as c-Met selective kinase inhibitors.
A novel quinoline derivative that selectively inhibits c-Met kinase was identified. The molecular design is based on a result of the analysis of a PF-2341066 (1)/c-Met cocrystal structure (PDB code: 2wgj). The kinase selectivity of the derivatives is discussed from the view point of the sequence homology of the kinases, the key interactions found in X-ray cocrystal structures, and the structure-activity relationship (SAR) obtained in this work.
Nishii
Hiroki
H
Department of Chemistry Research 2, Chugai Pharmaceutical Co, Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Chiba
Takashi
T
Morikami
Kenji
K
Fukami
Takaaki A
TA
Sakamoto
Hiroshi
H
Ko
Kwangseok
K
Koyano
Hiroshi
H
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015125:Oxyquinoline / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D015125:Oxyquinoline; D019859:Proto-Oncogene Proteins c-met