title: Pyrazolo[4,3-d]pyrimidine bioisostere of roscovitine: evaluation of a novel selective inhibitor of cyclin-dependent kinases with antiproliferative activity.
abstract: Inhibition of cyclin-dependent kinases (CDKs) with small molecules has been suggested as a strategy for treatment of cancer, based on deregulation of CDKs commonly found in many types of human tumors. Here, a new potent CDK2 inhibitor with pyrazolo[4,3-d]pyrimidine scaffold has been synthesized, characterized, and evaluated in cellular and biochemical assays. 7-Benzylamino-5(R)-[2-(hydroxymethyl)propyl]amino-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine, compound 7, was prepared as a bioisostere of the well-known CDK inhibitor roscovitine. An X-ray crystal structure of compound 7 bound to CDK2 has been determined, revealing a binding mode similar to that of roscovitine. Protein kinase selectivity profile of compound 7 and its biological effects (cell cycle arrest, dephosphorylation of the retinoblastoma protein, accumulation of the tumor suppressor protein p53, induction of apoptosis, inhibition of homologous recombination) are consistent with CDK inhibition as a primary mode of action. Importantly, as the anticancer activities of the pyrazolo[4,3-d]pyrimidine 7 exceed those of its bioisostere roscovitine, compound 7 reported here may be preferable for cancer therapy.
authors.affiliation: Laboratory of Growth Regulators, Faculty of Science, Palacký University and Institute of Experimental Botany ASCR, Olomouc, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.forename: Libor
authors.initials: L
authors.lastname: Havlícek
authors.forename: Iain W
authors.initials: IW
authors.lastname: McNae
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Jirí
authors.initials: J
authors.lastname: Voller
authors.forename: Antonín
authors.initials: A
authors.lastname: Sturc
authors.forename: Jana
authors.initials: J
authors.lastname: Navrátilová
authors.forename: Marek
authors.initials: M
authors.lastname: Kuzma
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrík
authors.forename: Jirí
authors.initials: J
authors.lastname: Bártek
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
authors.forename: Vladimír
authors.initials: V
authors.lastname: Krystof
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003460:Crystallization; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D011995:Recombination, Genetic; D000077546:Roscovitine; D013055:Spectrophotometry, Infrared
chemical_list: C559145:7-benzylamino-5-(2-(hydroxymethyl)propyl)amino-3-isopropyl-1(2)H-pyrazolo(4,3-d)pyrimidine; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases