Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity.
|Abstract||Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact w ... [truncated at 450 characters in length]|
|Author||Pogacic, Vanda; Bullock, Alex N; Fedorov, Oleg; et al|
|Subject||Animals Antineoplastic Agents Cell Line, Tumor Chemistry, Pharmaceutical Drug Design Enzyme Inhibitors Humans Inhibitory Concentration 50 Mice Models, Chemical Models, Molecular Protein Binding Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-pim-1 Pyridazines Structure-Activity Relationship pharmacology methods chemistry pharmacology antagonists and inhibitors antagonists and inhibitors chemistry|
SALMON: solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy.
|Abstract||Quinone oxidoreductase 2 (NQO2) binds the prodrug tretazicar (also known as CB1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide), which exhibits a profound antitumor effect in human cancers when administered together with caricotamide. X-ray structure determination allowed for two possible orientations of the ligand. Here we describe a new NMR method, SALMON (solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy) ... [truncated at 450 characters in length]|
|Author||Ludwig, Christian; Michiels, Paul J A; Wu, Xiaoqiu; et al|
|Subject||Antineoplastic Agents Aziridines Binding Sites Ligands Magnetic Resonance Spectroscopy Models, Molecular NAD(P)H Dehydrogenase (Quinone) Prodrugs Protein Binding Solvents Water chemistry chemistry chemistry chemistry chemistry|
Targeting group II PAKs in cancer and metastasis.
|Abstract||The p21 activated kinases (PAKs) play an essential role in cell signaling and control a variety of cellular functions including cell motility, survival, angiogenesis and mitosis. PAKs are important regulators in growth factor signaling, cytoskeletal reorganization and growth factor-mediated cell migration. Overexpression of PAKs has been detected in many cancers and linked to increased migration potential, anchorage independent growth and metasta ... [truncated at 450 characters in length]|
|Author||Eswaran, Jeyanthy; Soundararajan, Meera; Knapp, Stefan;|
|Subject||Animals Antineoplastic Agents Apoptosis Cell Transformation, Neoplastic Chemistry, Pharmaceutical Crystallography, X-Ray Cytoskeleton Drug Design Gene Expression Regulation, Neoplastic Humans Mitosis Neoplasm Metastasis Neoplasms Neurons p21-Activated Kinases pharmacology methods methods metabolism metabolism pathology metabolism metabolism|
Structural basis for substrate specificity in human monomeric carbonyl reductases.
|Abstract||Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a v ... [truncated at 450 characters in length]|
|Author||Pilka, Ewa S; Niesen, Frank H; Lee, Wen Hwa; et al|
|Subject||Alcohol Oxidoreductases Antineoplastic Agents Cloning, Molecular Crystallography, X-Ray Ethanolamines Humans Isoquinolines Kinetics Mutagenesis Mutagenesis, Site-Directed Structure-Activity Relationship Substrate Specificity Temperature Xenobiotics chemistry pharmacology methods chemistry chemistry chemistry|
Quinone oxidoreductase-2-mediated prodrug cancer therapy.
|Abstract||DNA-damaging agents are widely used in cancer treatment despite their lack of tumor specificity. Human NQO2 (quinone oxidoreductase-2) is an atypical oxidoreductase because no endogenous electron donor has been identified to date. The enzyme converts CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide], in the presence of the synthetic nicotinamide cofactor analog EP0152R, to a cytotoxic bifunctional alkylating agent. NQO2 activity in hepatocellular t ... [truncated at 450 characters in length]|
|Author||Middleton, Mark R; Knox, Richard; Cattell, Emma; et al|
|Subject||Adult Aged Antineoplastic Agents Aziridines Cell Death Cross-Linking Reagents Crystallography, X-Ray DNA, Neoplasm Enzyme Activation Female Humans Male Middle Aged Models, Molecular Neoplasms Prodrugs Quinone Reductases adverse effects chemistry pharmacokinetics therapeutic use adverse effects chemistry pharmacokinetics therapeutic use drug effects pharmacology metabolism drug effects drug therapy chemistry pharmacology therapeutic use chemistry metabolism|