About: Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity

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About: Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity Goto Sponge NotDistinct Permalink

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	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 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. 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 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. (en)
Title	Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity (en)
skos:prefLabel	Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity (en)
skos:notation	RIV/61989592:15310/11:10222088!RIV12-MZ0-15310___
http://linked.open...avai/predkladatel	Přírodovědecká fakulta
http://linked.open...avai/riv/aktivita	P Z
http://linked.open...avai/riv/aktivity	P(ED0007/01/01), P(ED0030/01/01), P(GA204/08/0511), P(GA301/02/0475), P(GA301/08/1649), P(GPP301/11/P554), P(IAA501370902), P(NS10282), P(NT11065), Z(AV0Z50200510), Z(AV0Z50380511), Z(MSM6198959216)
http://linked.open...iv/cisloPeriodika	8
http://linked.open...vai/riv/dodaniDat	2012
http://linked.open...aciTvurceVysledku	Jorda, Radek Voller, Jiří Havlíček, Libor Kryštof, Vladimír Strnad, Miroslav Navrátilová, Jana
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Univerzita Palackého v Olomouci / Přírodovědecká fakulta
http://linked.open...dnocenehoVysledku	225326
http://linked.open...ai/riv/idVysledku	RIV/61989592:15310/11:10222088
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	Activity; Antiproliferative; Kinases; Cyclin-Dependent; Inhibitor; Selective; Roscovitine; Bioisostere; Pyrazolo[4,3-d]pyrimidine (en)
http://linked.open.../riv/klicoveSlovo	Inhibitor Roscovitine Activity 3-d]pyrimidine Antiproliferative Bioisostere Cyclin-Dependent Kinases Pyrazolo[4 Selective
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[B24B4DCD7F7F]
http://linked.open...i/riv/nazevZdroje	Journal of Medicinal Chemistry
http://linked.open...in/vavai/riv/obor	CE
http://linked.open...ichTvurcuVysledku	6 (xsd:int)
http://linked.open...cetTvurcuVysledku	12 (xsd:int)
http://linked.open...vavai/riv/projekt	Biological activity of synthetic inhibitors of cyclin-dependent kinases Genomic integrity and instability mechanisms in the pathogenesis and potential personalized targeted treatment of prostate cancer. Biomedicine for regional development and human resources Centre of the Region Haná for Biotechnological and Agricultural Research Modulation of cell division of normal and cancer cells by cyclin-dependent kinase inhibitors Purine inhibitors of cyclin-dependent kinases as anticancer and antimitotic compounds Modulation of poly-ADP-ribosylation in DNA damage response and targeted treatment Cellular responses to replication stress: Mechanisms and the role of fragile sites in genomic instability Analysis and targeting of DNA damage signaling and repair mechanisms in glioblastomas and glioblastoma stem cells as a strategy to elucidate pathogenesis and search for individualized targeted treatments combined with standard therapy
http://linked.open...UplatneniVysledku	2011
http://linked.open...v/svazekPeriodika	54
http://linked.open...iv/tvurceVysledku	Kuzma, Marek Kryštof, Vladimír Navrátilová, Jana BÁRTEK, Jiří HAVLÍČEK, Libor JORDA, Radek MISTRÍK, Martin McNae, Iain STRNAD, Miroslav VOLLER, Jiří Walkinshaw, Malcolm Šturc, Antonín
http://linked.open...ain/vavai/riv/wos	000289697800033
http://linked.open...n/vavai/riv/zamer	Microorganisms in Research and Biotechnology Mechanismy regulace růstu a vývoje rostlin na úrovni buněk, orgánů a celých organismů: fyziologické, genetické a molekulárně biologické základy Modulation of signalling and regulatory pathways in normal and cancer cells
issn	0022-2623
number of pages	14 (xsd:int)
http://bibframe.org/vocab/doi	10.1021/jm200064p
http://localhost/t...ganizacniJednotka	15310
is http://linked.open...avai/riv/vysledek of	Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity

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