Abstract
Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.
Highlights
The 20 members of cyclin-dependent kinase (CDK) family known to this day regulate the cell cycle, transcription and splicing [1]
The results reveal that certain protein kinases such as CDK6, receptor-type tyrosine-protein kinase (RTK, FLT3, CD135), coagulation factor II receptor (PAR1), RAC-b serine/threonine-protein kinase (AKT2), mitogen-activated protein kinase 14 (MAPK14, p38a) and bacterial cell membrane nonspecific serine/threonine protein kinase (STK1) favor a classical DFG-out conformation even without the presence of type II inhibitor [79,80], whereas the other inactive, unphosphorylated kinases can be shown to assume the DFG-in conformation [81]
CDKs and their cyclin partners is observed in a range of tumor types, and some of ulation of CDKs and their cyclin partners is observed in a range of tumor types, and some them have emerged as promising therapeutic targets in cancer
Summary
Schematic representation representation of different shown blue,the with the Asp-Phe-Gly in green. The particular regions different types of inhibitors are residue of theofDFG motif.motif. Wherewhere different types of inhibitors bind arebind described described below, the allosteric pocket is only a visualization and its place can be anywhere outside below, the allosteric pocket is only a visualization and its place can be anywhere outside the ATP the ATP binding site
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