ABSTRACT
To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Thiazoles/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzamides/pharmacokinetics , Benzamides/pharmacology , Benzoates/chemical synthesis , Benzoates/pharmacokinetics , Benzoates/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Molecular Structure , Phosphorylation , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A 75-year-old man, who had eaten wild boar and deer repeatedly until November 2006, visited our hospital because of a right pleural effusion on chest X-ray films after he bruised a hip in January 2007. A right thoracocentesis revealed exudative pleural effusion with many neutrophils. Ten days after his first visit, a pleural biopsy specimen suggested the existence of parasite eggs. Twenty-six days after his first visit, he was admitted to our hospital because of leukocytosis, increased systemic inflammatory markers and a right pleural effusion. We found a great number of neutrophils, eggs of the Paragonimus species and gram-positive cocci in the pleural effusion. Streptococcus pneumoniae was also identified in his pleural effusion. In addition, a diagnosis of Paragonimiasis westermani was made serological study. After the continuous drainage of the pleural effusion, the patient was treated with praziquantel and antibiotics, and he gradually improved.
