Title:Cyclin-dependent kinase Inhibitors Inspired by Roscovitine: Purine Bioisosteres
VOLUME: 18 ISSUE: 20
Author(s):Radek Jorda, Kamil Paruch and Vladimir Krystof
Affiliation:Laboratory of Growth Regulators, Palacky University, Slechtitelu 11, 78371, Olomouc, Czech Republic.
Keywords:Cancer, cyclin-dependent kinase, inhibitor, roscovitine, bioisostere, oncogenes, purine, clinical trials, enantiomers, CDK active site
Abstract:Roscovitine is a synthetic inhibitor of cyclin-dependent kinases that is currently undergoing clinical trials as a candidate drug
for some oncological indications. Its discovery prompted many research teams to further optimize its structure or to initiate their own related
but independent studies. This article reviews known roscovitine bioisosteres that have been prepared as CDK inhibitors using different
core heterocycles. The individual bioisostere types have been described and explored to a different extent, which complicates direct
comparisons of their biochemical activity - only six direct analogs containing different purine bioisosteres have been prepared and
evaluated side by side with roscovitine. Only four types of bioisosteres have demonstrated improved biological properties, namely pyrazolo[
1,5-a]-1,3,5-triazines, pyrazolo[1,5-a]pyrimidines, pyrazolo[1,5-a]pyridines and pyrazolo[4,3-d]pyrimidines.
