casein-kinase-ii and pyrazole

Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug target for nephritis and cancers, while CK2α2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2α1 and CK2α2 make it difficult to design CK2α1-specific inhibitors. Herein, the crystal structures of CK2α1 and CK2α2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein-inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2α1, but not to CK2α2, at the CK2β protein-protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2α1 inhibitors.

Topics: Adenosine Triphosphate; Casein Kinase II; Isoenzymes; Protein Kinase Inhibitors; Pyrazoles

Densely functionalised pyrazole carboxamides and carboxylic acids were synthesised in an expedient manner through saponification and transamidation, respectively, of ester-functionalised pyrazoles. This synthetic protocol allowed for three diversifying steps in which appendages on the pyrazole scaffold were adjusted to optimise inhibition of protein kinases. Thirty-five analogues were tested in CK2, AKT1, PKA, PKCalpha, and SAPK2a (p38) kinase inhibition bioassays. Blocking of these kinases may lead to effective therapies for treating inflammatory diseases and cancer. In order to investigate potential biological activity, MCF-7 human breast cancer cells were incubated with the most promising derivatives. Two analogues caused changes in MCF-7 cell growth, one of them through cell cycle arrest demonstrated by cell cycle analysis.

Topics: Amides; Breast Neoplasms; Carboxylic Acids; Casein Kinase II; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclic AMP-Dependent Protein Kinases; Female; Humans; Mitogen-Activated Protein Kinase 14; Protein Kinase C-alpha; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Signal Transduction