5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases

0459351 - ÚEB 2017 RIV FR eng J - Článek v odborném periodiku
Vymětalová, Ladislava - Havlíček, Libor - Šturc, Antonín - Skrášková, Zuzana - Jorda, Radek - Pospíšil, Tomáš - Strnad, Miroslav - Kryštof, Vladimír
5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases.
European Journal of Medicinal Chemistry. Roč. 110, MAR 3 (2016), s. 291-301. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MŠMT(CZ) LO1204; GA ČR(CZ) GA15-15264S
Institucionální podpora: RVO:61389030
Klíčová slova: Cyclin-dependent kinase * Inhibitor * Selectivity
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 4.519, rok: 2016

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 C-terminus 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.
Trvalý link: http://hdl.handle.net/11104/0259567