CDK inhibition and cancer therapy
Introduction
Mammalian cell division is regulated by the timely and coordinated activation of the cyclin-dependent kinase (CDK) family. Regulation of CDK activity occurs at multiple levels, including cyclin synthesis and degradation; activating and inactivating phosphorylation events; CDK inhibitor protein synthesis, binding and degradation; and subcellular localization (1, 2, 3, 4, 5; see Figure 1). Undoubtedly with the magnitude of research directed at CDKs, further insights into novel mechanisms of their regulation will be revealed. Regulation of CDK activity is essential to the ordered execution of the processes that govern cell growth, complete DNA replication and mitotic transfer of the genome to new daughter cells. To ensure this, surveillance mechanisms function as checkpoints to control cell-cycle progression in case the conditions for advancement have not been met 6, 8, 9•, 10. As one of their functions, these signaling pathways exert their effects on cell-cycle progression through CDK regulation. Similarly, as part of their function, growth-promoting signal transduction pathways must transmit their effects on cell-cycle progression by modulating CDK activity 11, 12, 13, 14. As with components of these signal transduction pathways that are so often genetically altered in human cancers, it is befitting that CDKs, their regulators, and substrates, are also frequently the targets of genetic lesions, and promote neoplastic transformation 15, 16. The best-characterized case of such alteration is the retinoblastoma (RB) pathway. Under normal conditions, phosphorylation of pRb by the Cdk4 or Cdk6 enzyme in complex with one of the D-type cyclins are required for G1→S phase transition. Conversely, pRb’s unphosphorylated state is essential for mitotic division cycle exit. Cdk4 and Cdk6 are specifically inhibited by the INK4 small molecular weight CDK inhibitor family. It is noted that alterations in one or another component of this pathway is found in nearly all human cancers 15, 16, 17.
Excellent reviews have recently documented the multiple modes of CDK regulation, interactions between CDK regulatory pathways and checkpoint control mechanisms and oncogenic alterations of cell-cycle components. Our attempt here is to illustrate the potential for development of therapeutics to treat human cancers by interfering with cell-cycle progression. Because of the central role that they play in advancing the division cycle, CDKs have been targeted for drug discovery and a number of small molecule compounds have now been identified as CDK inhibitors. These strategies and other targets of intervention within the cell cycle are discussed in our review.
Section snippets
Approaches to CDK inhibition
Because of the complex nature of its regulation, modulating CDK activity can be approached via multiple modes for therapeutic intervention. Two basic schemes to inhibit cyclin-dependent kinases are to either directly block the catalytic activity of the CDK, or to target the major regulators of their activity. The most extensively examined of these is catalytic inhibition, which has produced both chemical and peptide/protein based CDK inhibitors. Regulators of CDK activity amenable to
CDK inhibition: growth arrest, senescence and apoptosis
There are a number of ways to study the role of CDKs in the cell, the simplest being to assess the cellular response to CDK inhibition. In yeast, the power of genetics and the regulation of cell cycle by a single CDK enzyme has been invaluable in understanding the consequences of loss of CDK activity. In human cells, however, the complexity of the CDK family and the programmed suicide system (apoptosis) triggered in response to growth and cell-cycle perturbations, combined with the multitude of
Summing up and the future for CDK inhibitors
We have outlined the potential therapeutic value of CDK inhibition as a cancer treatment and presented the approaches taken to investigate this possibility. To date, only the chemical inhibitor flavopiridol has reached clinical trials and it has yet to be proven whether its effects are caused by CDK inhibition. Specificity of these compounds is a key factor and one of the future challenges will be to generate more potent and specific CDK inhibitors. Further crystallographic studies of CDKs with
Future prospects
In line with the prevailing CDK-centric view of the cell-division cycle is the fact that the majority of therapeutics under development that target cell-cycle regulation have thus far been CDK inhibitors. Modulators of CDK activity, however, offer as good or greater potential as targets for intervention. As discussed earlier, a number of CDK-activating enzymes (such as CAK and Cdc25 phosphatases) and inhibitory enzymes (such as Wee1 and Myt1) as well as enzymes involved in modulating their
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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