Activation of wild-type p53 by MDM2 inhibitors: a new strategy for lymphoma treatment

Pujals, Anaïs; Favre, Loëtitia; Gaulard, Philippe; Wiels, Joëlle

doi:10.2147/blctt.s60486

Cited by 2 publications

(2 citation statements)

References 66 publications

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“…The p53 pathway is induced not just by DNA damage but also by ribosomal stress and oncogene-induced stress [48]. These signals act through MDM2 to change the levels and activity of p53 and block the p53-MDM2 interaction which is sufficient to induce tumor regression [17] and trigger significant ligand-induced changes in MDM2 [49]. While inducing p53 through ionizing radiation or systemic DNA damage is highly toxic to normal tissue, systemic treatment with small molecule inhibitors of p53-MDM2 interaction is only toxic to tumor tissue and not to normal tissue.…”

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

et al. 2016

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As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53-MDM2 protein-protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53-MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure-activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer. Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53-MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure-activity relationship.

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Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

et al. 2016

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“…Inactivation of the p53 pathway-be it through mutations of the p53 gene itself, mutations of genes encoding key p53 regulators, and/or binding partners, or other means-is a common, if not universal feature of human cancers. The cancers in which p53 is not mutated, but rather aberrantly kept at low levels at all times by means of overexpressed negative regulators [15,16], have better chances of being defeated because, if p53 levels could be brought back to normal, its target genes could be activated. Indeed, reactivation of the endogenous p53 signaling pathway has been shown to lead to tumor regression [17,18].…”

Section: Introductionmentioning

confidence: 99%

Engineering Optogenetic Control of Endogenous p53 Protein Levels

Wehler

Ventura

2019

Applied Sciences

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The transcription factor p53 is a stress sensor that turns specific sets of genes on to allow the cell to respond to the stress depending on its severity and type. p53 is classified as tumor suppressor because its function is to maintain genome integrity promoting cell cycle arrest, apoptosis, or senescence to avoid proliferation of cells with damaged DNA. While in many human cancers the p53 gene is itself mutated, there are some in which the dysfunction of the p53 pathway is caused by the overexpression of negative regulators of p53, such as Mdm2, that keep it at low levels at all times. Here we develop an optogenetic approach to control endogenous p53 levels with blue light. Specifically, we control the nuclear localization of the Mmd2-binding PMI peptide using the light-inducible export system LEXY. In the dark, the PMI-LEXY fusion is nuclear and binds to Mdm2, consenting to p53 to accumulate and transcribe the target gene p21. Blue light exposure leads to the export of the PMI-LEXY fusion into the cytosol, thereby Mdm2 is able to degrade p53 as in the absence of the peptide. This approach may be useful to study the effect of localized p53 activation within a tissue or organ.

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Activation of wild-type p53 by MDM2 inhibitors: a new strategy for lymphoma treatment

Cited by 2 publications

References 66 publications

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

Engineering Optogenetic Control of Endogenous p53 Protein Levels

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