Cyclin-dependent kinase inhibitors inspired by roscovitine: purine bioisosteres.

Radek Jorda, Kamil Paruch, Vladimír Krystof

Laboratory of Growth Regulators, Palacky University, Slechtitelu 11, 78371, Olomouc, Czech Republic.

Current pharmaceutical design 2012

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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.

Citation

Radek Jorda, Kamil Paruch, Vladimír Krystof. Cyclin-dependent kinase inhibitors inspired by roscovitine: purine bioisosteres. Current pharmaceutical design. 2012;18(20):2974-80