ABSTRACT
We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrrolidines/chemical synthesis , Triazines/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors , Dogs , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Isoenzymes/antagonists & inhibitors , Lung Neoplasms/drug therapy , Mice , Mice, Nude , Models, Molecular , Molecular Conformation , Neoplasm Transplantation , Protein Binding , Pyrrolidines/pharmacology , Rats , Structure-Activity Relationship , Triazines/pharmacologyABSTRACT
Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot be explained by cytoskeletal mechanisms. In the present study submicromolar concentrations of taxol, mimicking concentrations found in patients, induced cytosolic calcium (Ca(2+)) oscillations in a human neuronal cell line. These oscillations were independent of extracellular and mitochondrial Ca(2+) but dependent on intact signaling via the phosphoinositide signaling pathway. We identified a taxol binding protein, neuronal Ca(2+) sensor 1 (NCS-1), a Ca(2+) binding protein that interacts with the inositol 1,4,5-trisphosphate receptor from a human brain cDNA phage display library. Taxol increased binding of NCS-1 to the inositol 1,4,5-trisphosphate receptor. Short hairpin RNA-mediated knockdown of NCS-1 in the same cell line abrogated the response to taxol but not to other agonists stimulating the phosphoinositide signaling pathway. These findings are important for studies involving taxol as a research tool in cell biology and may help to devise new strategies for the management of side effects induced by taxol therapy.
Subject(s)
Calcium Signaling/drug effects , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Neuronal Calcium-Sensor Proteins/metabolism , Neuropeptides/metabolism , Paclitaxel/pharmacology , Biotin/chemistry , Calcium/metabolism , Cell Line, Tumor , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Humans , Neuroblastoma/metabolism , Neuronal Calcium-Sensor Proteins/genetics , Neuropeptides/genetics , Paclitaxel/chemistry , RNA InterferenceABSTRACT
We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small molecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as kinase inhibitors. The 3-(2-(1-pyrrolidinyl)ethoxy)phenyl analogue (43) was identified as one of the most potent inhibitors of Src kinase.
