Vymetalová L., Havlíček L., Šturc A., Skrášková Z., Jorda R., Pospíšil T., Strnad M., Kryštof V.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 110: 291-301, 2016

Keywords: Cyclin-dependent kinase Inhibitor Selectivity Bioisostere
Abstract: A series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine derivatives was synthesized and evaluated for their cyclin-dependent kinase (CDK) inhibition activity. The most potent compounds contained various hydroxyalkylamines at the 5 position and possessed low nanomolar IC50 values for CDK2 and CDK5. Preliminary profiling of one of the most active compounds on a panel of 50 protein kinases revealed its high selectivity for CDKs. The compounds arrested cells in S and G2/M phases, and induced apoptosis in various cancer cell lines. Significant dephosphorylation of the Cterminus of RNA polymerase II and focal adhesion kinase (FAK), well-established substrates of CDKs, has been found in treated cells. Cleavage of PARP-1, down-regulation of Mcl-1 and activation of caspases correlated well with CDK inhibition and confirmed apoptosis as the primary type of cell death induced in cancer cells treated with the compounds in vitro. A comparison of known purine-based CDK inhibitor CR8 with its pyrazolo[4,3-d]pyrimidine bioisosteres confirmed that the novel compounds are more potent in cellular assays than purines. Therefore, pyrazolo[4,3-d]pyrimidine may emerge as a novel scaffold in medicinal chemistry and as a source of potent CDK inhibitors
DOI: IEB authors: Libor Havlíček, Vladimír Kryštof, Miroslav Strnad