MAPK-specific tyrosine phosphatases: new targets for drug discovery?
|Abstract||Protein tyrosine phosphatases (PTPs) have key roles in a diverse range of cellular processes, and their dysregulation is associated with several human diseases. Many PTPs are recognized as potential drug targets; however, inhibitor development has focused only on a small number of enzymes, most notably PTP1B for type II diabetes and obesity, and MKP1 and CDC25 for cancer. The future challenge of selective-inhibitor development for PTPs will be si ... [truncated at 450 characters in length]|
|Author||Barr, Alastair J; Knapp, Stefan;|
|Subject||Animals Crystallography, X-Ray Drug Design Humans Mitogen-Activated Protein Kinase Kinases Models, Molecular Phosphorylation Protein Tyrosine Phosphatases chemistry metabolism physiology chemistry metabolism physiology|
Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design.
|Abstract||Glutamine synthetase (GS) catalyzes the ligation of glutamate and ammonia to form glutamine, with concomitant hydrolysis of ATP. In mammals, the activity eliminates cytotoxic ammonia, at the same time converting neurotoxic glutamate to harmless glutamine; there are a number of links between changes in GS activity and neurodegenerative disorders, such as Alzheimer's disease. In plants, because of its importance in the assimilation and re-assimilat ... [truncated at 450 characters in length]|
|Author||Krajewski, Wojciech W; Collins, Ruairi; Holmberg-Schiavone, Lovisa; et al|
|Subject||Adenosine Triphosphate Amino Acid Sequence Animals Apoenzymes Binding Sites Catalytic Domain Cloning, Molecular Crystallography, X-Ray Dogs Drug Design Drug Interactions Glutamate-Ammonia Ligase Herbicides Humans Hydrogen Bonding Kinetics Ligands Magnesium Models, Chemical Models, Molecular Molecular Sequence Data Pharmaceutical Preparations Protein Binding Protein Conformation Protein Structure, Tertiary Sequence Homology, Amino Acid Substrate Specificity Temperature metabolism pharmacology chemistry chemistry genetics isolation and purification metabolism chemical synthesis chemistry metabolism pharmacology chemical synthesis chemistry|
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|
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|
Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.
|Abstract||The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2.|
|Author||Bullock, Alex N; Russo, Santina; Amos, Ann; et al|
|Subject||Binding Sites Chemistry, Pharmaceutical Crystallography, X-Ray Drug Design Enzyme Inhibitors Humans Molecular Structure Protein Conformation Protein Isoforms Protein Structure, Tertiary Proto-Oncogene Proteins c-pim-1 Ruthenium Staurosporine Structure-Activity Relationship methods methods chemistry chemistry chemistry chemistry|