ATP-site directed inhibitors of cyclin-dependent kinases.
Cyclin-dependent kinases trigger and coordinate transitions between different phases the cell division cycle (CDK1, 2, 3, 4, 6, 7). They also play a role in apoptosis (CDK2), in neuronal cells (CDK5) and in the control of transcription (CDK 7, 8, 9). Intensive screening has lead to the recent identification of a series of chemical inhibitors of CDKs: olomoucine, roscovitine, purvalanol, CVT-313, flavopiridol, g-butyrolactone, indirubins, paullones and staurosporine. Some of these compounds display remarkable selectivities and efficiencies (IC50 < 25 nM). Many have been co-crystallised with CDK2 and their interactions with the kinase have been analysed in atomic detail. These inhibitors all act by competing with ATP for binding at the catalytic site. Most inhibitors present a flat heterocyclic ring system that occupies the purine binding pocket as well as form 2 or 3 hydrogen bonds with Glu-81 and Leu-83. The binding modes of these inhibitors are reviewed in this article. Knowledge of the CDK/inhibitor interactions will be of great help to design inhibitors with improved selectivity our potency as well as to generate affinity chromatography matrices for the purification and identification of their cellular targets. The potential use of CDK inhibitors is being extensively evaluated in cancer chemotherapy and other fields such as the cardiovascular domain (restenosis), dermatology (psoriasis), nephrology (glomerulonephritis) parasitology (unicellular parasites such as Plasmodium, Trypanosomes, Toxoplasm,.etc.), neurology (Alzheimer's disease) and viral infections (cytomegalovirus, H.I.V., herpes).
Gray
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University of California, Department of Chemistry, 824 Latimer Hall, Berkeley, California, USA.
Détivaud
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Doerig
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Meijer
L
L
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry; D006801:Humans; D007541:Isopentenyladenosine; D007701:Kinetin; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry; D011687:Purines / Q000737:chemistry; D000077546:Roscovitine; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019311:Staurosporine / Q000737:chemistry; D013498:Suramin / Q000737:chemistry
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011687:Purines; D000077546:Roscovitine; C001478:N(6)-(delta(2)-isopentenyl)adenine; C077990:alvocidib; D013498:Suramin; C090046:olomoucine; D007541:Isopentenyladenosine; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine; D000225:Adenine; D007701:Kinetin