Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Zhao, Yujun; Bernard, Denzil; Wang, Shaomeng

doi:10.7750/biodiscovery.2013.8.4

Cited by 61 publications

(65 citation statements)

References 82 publications

(112 reference statements)

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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%

“…Small molecules can penetrate the cell membrane to interact with targets inside a cell and are designed to interfere with the enzymatic activity of the target protein [16]. Knowledge of the 3-D structure of large target protein macromolecules by X-ray crystallography permits the rational design of small molecules that mimic the stereochemical features of the macromolecule functional domains and generate virtual libraries of potential drug molecules to be used for in silico screening [17]. Therefore, small molecule inhibitors have emerged as a crucial component of therapy for many types of malignancies, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma [17][18][19].…”

Section: Spiro-oxindole Lead Compoundmentioning

confidence: 99%

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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%

Section: Spiro-oxindole Lead Compoundmentioning

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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“…Indeed for p53 targeting, cis-imidazoline analogs, Nutlins have been developed to mimic the p53 a-helix within the TAD ( Figure 5). Thus these small molecules are able to bind really specifically to the hydrophobic cleft of MDM2 and block the interaction between MDM2 and p53 which activates this latter [56,57]. New leads for therapeutic use could be obtain by designing small molecules targeting PPIs, approach which requires learning more about them through intrinsically disorder structures.…”

Section: Targeting Ppis To Turn On P53mentioning

confidence: 99%

Evolution of Conformational Disorder & Diversity of the P53 Interactome

Huart¹,

Hupp²

2013

Biodiscovery

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The tumour suppressor p53 is now known to be an ancient transcription factor that had already evolved interaction sites with its partner protein MDM2 at the dawn of multi-cellular eukaryotic animal life. The billionyear life history of the p53-MDM2 axis has permitted significant time for the proteins to integrate into a distinct range of cellular pathways including binding to hundreds of genomic promoters and regulatory protein-protein interactions with hundreds of distinct functions. This long age of p53 allows us to understand how the protein can regulate a range of functions such as energy generation of the cell, cell motility, genome integrity, virus infection, immune cell response, ageing, and oxidative stress. Due to this deep integration of p53 into the core of eukaryotic life, it is not surprising that the p53 pathway requires inactivation in order for human cancer cells to evade the normal growth controlling processes that have been shaped through evolution by natural selection. This review will focus on the emerging concepts in the protein science field that shed light on p53 protein evolution and function including the nature of thermodynamically unstable regulatory proteins and the growing realisation that the majority of protein-protein interactions in complex eukaryotic cells are driven by intrinsically unstructured and weakly interacting peptide motifs. These concepts help to explain how the vast number of dynamic and specific protein-protein interactions in the p53 pathway evolved, suggest how amino acid modifications like phosphorylation or acetylation in turn evolved to regulate dynamically the p53 interactome, and finally reveal therapeutic strategies for targeting the p53 interactome in human cancers. Intrinsic disorder: the rise of a new dogma in protein science that impacts upon our understanding of p53As biologists or biochemists, we have all learned the structure-function paradigm that proteins display different levels of organisation: a "primary" linear sequence on which depends local spatial "secondary" arrangements stabilised by a three dimensional compact structure, usually referred as globular protein or called native fold, i.e. the biologically active form of the protein. Upon this structure-function concept several protein-protein interaction (PPI) models have been developed such as the recent Nobel Prize awarded on solving the structure of a ribosome. It is perhaps not a co-incidence that a major advance on the road to acquire the structure of this prokaryotic multi-protein complex was the decision to switch to purifying ribosomal proteins from thermophilic bacteria which are more suitable to form stable structures using current experimental methodologies. More "unstable" ribosomal complexes from, for example, higher eukaryotes are not suitable for such crystallographic

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“…However, MI-219 is an orally available compound that exhibits good pharmacokinetic and pharmacodynamics properties (oral bioavailability of 65% in rats compared to 10% for MI-63). 49 In vitro and in vivo results obtained by Shangary et al show that MI-219 activates p53 and induces cell-cycle arrest in both normal and tumoral cells, but apoptosis only occurs in the latter.…”

Section: Antioncogenic Activity Of Spirooxindoles In B-cell Lymphomamentioning

confidence: 99%

“…RG7112 is resistant to oxidation, which had been a problem with earlier drugs, has a reduced molecular weight, decreased metabolic liability, and binds to MDM2 with an affinity of 11 nM compared to 90 nM for nutlin 3. 49 Therefore, RG7112 is three times more potent than nutlin 3 in inhibition of cell growth. The first published results of these trials come from a proof-of-mechanism study performed in patients with amplified MDM2 liposarcoma.…”

Section: Clinical Trials With Mdm2 Inhibitors In Hematological Malignmentioning

confidence: 99%

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

Pujals¹,

Favre²,

Gaulard³

et al. 2015

BLCTT

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Abstract:The tumor suppressor TP53 is frequently mutated or inactivated in human cancers. Mutations of TP53 are less common in lymphomas than in other tumors, but the protein is often inhibited by the overexpression of its main regulator -MDM2. In the past 10 years, major efforts have been made to develop drugs that can reactivate p53 and restore its functions. This review focuses on recent advances in the development of small inhibitors of MDM2, which are potentially relevant for the treatment of B-and T-cell lymphomas. We will describe the current state of development of these drugs and discuss their mechanism of action in these hematological malignancies.

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Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New Cancer Therapeutics

Cited by 61 publications

References 82 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

Evolution of Conformational Disorder & Diversity of the P53 Interactome

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

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