Review
MDM2 inhibitors for cancer therapy

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The tumor suppressor p53 is a powerful antitumoral molecule frequently inactivated by mutations or deletions in cancer. However, half of all human tumors express wild-type p53, and its activation by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy. Proof-of-concept experiments have demonstrated the feasibility of this approach in vitro but the development of pharmacological inhibitors has been challenging. Recently, potent and selective small-molecule MDM2 inhibitors have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation is a viable alternative to current cytotoxic chemotherapy but clinical validation is still pending. Here, the new developments in the quest for pharmacological p53 activators are reviewed with an emphasis on small-molecule inhibitors of the p53–MDM2 interaction.

Section snippets

p53 as a therapeutic target

Nearly 40 000 articles published in the past 26 years have established the tumor suppressor p53 as one of the most important molecules in human cancer 1, 2. The main function of p53 is to organize cell defence against cancerous transformation. In this complex role, p53 coordinates a signal transduction network, the p53 pathway, that evolved to minimize the consequences of oncogenic stress 3, 4. p53 is a potent transcription factor that is activated in response to diverse stresses, leading to

MDM2: a master regulator of p53 stability and activity

The tumor suppressor p53 is a potent anti-proliferative and pro-apoptotic protein that can harm normal cells. This is why the cellular level of p53 is accurately controlled in unstressed cells. It has been well established that MDM2 has a major role in this regulation. p53 and MDM2 form an autoregulatory feedback loop by which the two proteins mutually control their cellular levels (Figure 2). p53 binds to the promoter and regulates the expression of the Mdm2 gene, one of its transcription

Antagonizing MDM2 function to activate p53

A large body of evidence has established MDM2 as a crucial negative regulator of p53 and the major suppressor of p53 function in tumors with aberrant MDM2 expression 33, 34. Thus, by liberating p53 from MDM2 one might stabilize the tumor suppressor and activate the p53 pathway, leading to growth arrest and apoptosis. This hypothesis has been tested by several experiments using macromolecular tools (reviewed in 35, 36, 37, 38). Collectively, the data from these studies suggest that, once freed

Small-molecule inhibitors of the p53–MDM2 interaction

An increasing number of small-molecule MDM2–p53 binding inhibitors have been discovered and published in the past three years (reviewed in 37, 48, 49). Here, only recent compounds are examined that have acceptable cellular potency and selectivity for their molecular target and might represent viable leads for development of therapeutic agents.

The first potent and selective small-molecule MDM2 antagonists, the nutlins (Figure 4), were identified from a class of cis-imidazoline compounds [50].

MDM2 inhibitors as antitumoral agents

Both in vitro and in vivo studies conducted with nutlins confirmed the antitumoral potential of the p53–MDM2 inhibitory approach, but also revealed that its effectiveness is likely to depend on TP53 mutation status and on the functionality of the p53 pathway in human tumors. Most p53 mutations in human cancer drastically affect the ability of p53 to bind its recognition DNA sequence in the promoters of p53 target genes. As a result, mutant p53 is usually inactive as a transcription factor 2, 61

Toxicity of p53 activation to normal tissues

One of the key issues regarding the therapeutic utility of pharmacological p53 activation is p53 toxicity to normal tissues. It has been well established that DNA-damage-activated p53 induces cell-cycle arrest and apoptosis in sensitive animal tissues [69]. These include the hematopoietic system, intestinal epithelium and other organs with a high proliferative index. This is expected because one of the p53 functions is to eliminate heavily damaged cells. However, one can speculate that, if p53

Single agent or combination therapy

Multiple forms of stress can activate the p53 pathway. DNA damage is one of the most effective p53 activators, and the p53 response has an important role in the mechanism of action of many currently used genotoxic chemotherapeutics [1]. However, genotoxic agents are known also to induce p53-independent mechanisms and can cause severe side effects. Also, by imposing a high genotoxic burden to normal tissues, treatment with therapeutic doses of genotoxins frequently leads to development of

MDM2 inhibitors as chemoprotective agents

Drugs that can arrest cell-cycle progression before entry into a particular phase can protect proliferating cells from agents that require transition through this phase for their activity 81, 82. For example, mitotic inhibitors only work on actively dividing cells. Thus, one might be able to protect normal proliferating tissues by manipulating their cell cycle during chemotherapy. It has been shown that p53-induced G1 arrest by genotoxic drugs (e.g. doxorubicin) can partially protect

Concluding remarks

Activation of the p53 tumor suppressor pathway in malignant tumors has been considered an attractive approach to cancer therapy but its clinical potential is still unknown. Of the several possible intervention points, most efforts have been invested in the development of MDM2 inhibitors for tumors that express wild-type p53. Recently, the first potent and selective inhibitors of the p53–MDM2 interaction, the nutlins, have been identified, followed by several other promising new classes of MDM2

Acknowledgments

The author thanks Bradford Graves and Nader Fotouhi for their help with the figures and David Heimbrook for critically reading the manuscript.

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