Coming full circle: cyclin-dependent kinases as anti-cancer drug targets.
Because the normal control of cell proliferation is disturbed in cancer, the cyclin-dependent kinases (CDKs) that trigger DNA synthesis and mitosis have been popular targets for inhibition with small molecules, but the jury is still out on whether this will be an effective anti-tumor strategy. There is debate about which of the multiple CDKs active during the mammalian cell cycle might be good targets, reflecting fundamental confusion about what, precisely, those different CDKs really do. In the classical view, based largely on their activation timing in cycling cells, different CDKs are specialized to perform discrete functions during distinct cell-cycle intervals. A revisionist model has emerged in which all functions essential to cell division can be performed by a single catalytic subunit, based on the ability of cells to proliferate and animals to survive when individual CDKs are removed by gene deletion or depleted by RNA interference. That those situations in no way resemble ones in which CDKs are inhibited pharmacologically is often overlooked or downplayed. A more nuanced - and accurate - picture is now coming into view, thanks to recent studies that reveal kinetically distinct pathways of activation for closely related CDKs and CDK-specific roles in the temporal control of S phase. The basic question of whether CDKs can be effectively targeted in cancer has yet to be answered but can now be addressed in chemical-genetic model systems that approximate the situation - still hypothetical - of truly selective CDK inhibition in vivo.
Fisher
Robert P
RP
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, USA, robert.fisher@mssm.edu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015003:Yeasts / Q000166:cytology
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases