The p53-MDM2/MDMX axis – A chemotype perspective

Khoury, Kareem; Popowicz, Grzegorz M.; Holak, Tad A.; Dömling, Alexander

doi:10.1039/c0md00248h

Cited by 67 publications

(49 citation statements)

References 63 publications

(130 reference statements)

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“…23 By now, numerous small-molecule compounds typically incorporating a heterocyclic core, as well as peptidomimetic inhibitors, have been identified to disrupt the p53-Mdm2 binding. 4,29 All of these compounds are, however, far less potent in reactivating the p53 pathway in vivo. One possible reason is the increase in expression of the other crucial negative regulator of p53, Mdm4.…”

Section: F2h Versus Other P53-mdm2 Cellular Assaysmentioning

confidence: 99%

The Fluorescent Two-Hybrid Assay to Screen for Protein–Protein Interaction Inhibitors in Live Cells: Targeting the Interaction of p53 with Mdm2 and Mdm4

Yurlova¹,

Derks

Buchfellner

et al. 2014

SLAS Discovery

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Protein–protein interactions (PPIs) are attractive but challenging targets for drug discovery. To overcome numerous limitations of the currently available cell-based PPI assays, we have recently established a fully reversible microscopy-assisted fluorescent two-hybrid (F2H) assay. The F2H assay offers a fast and straightforward readout: an interaction-dependent co-localization of two distinguishable fluorescent signals at a defined spot in the nucleus of mammalian cells. We developed two reversible F2H assays for the interactions between the tumor suppressor p53 and its negative regulators, Mdm2 and Mdm4. We then performed a pilot F2H screen with a subset of compounds, including small molecules (such as Nutlin-3) and stapled peptides. We identified five cell-penetrating compounds as potent p53–Mdm2 inhibitors. However, none exhibited intracellular activity on p53–Mdm4. Live cell data generated by the F2H assays enable the characterization of stapled peptides based on their ability to penetrate cells and disrupt p53–Mdm2 interaction as well as p53–Mdm4 interaction. Here, we show that the F2H assays enable side-by-side analysis of substances’ dual Mdm2–Mdm4 activity. In addition, they are suitable for testing various types of compounds (e.g., small molecules and peptidic inhibitors) and concurrently provide initial data on cellular toxicity. Furthermore, F2H assays readily allow real-time visualization of PPI dynamics in living cells.

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Section: F2h Versus Other P53-mdm2 Cellular Assaysmentioning

confidence: 99%

The Fluorescent Two-Hybrid Assay to Screen for Protein–Protein Interaction Inhibitors in Live Cells: Targeting the Interaction of p53 with Mdm2 and Mdm4

Yurlova¹,

Derks

Buchfellner

et al. 2014

SLAS Discovery

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“…Several reviews [39][40][41][44][45][46][47][48][49][50] have discussed progress on the development of MDM2 inhibitors. In this review, we will focus on structure-based strategies for the design of small molecule MDM2 inhibitors and summarize the current progress in the design of MDMX inhibitors.…”

Section: Blocking Mdm2-p53 and Mdmx-p53 Interactions As New Cancer Thmentioning

confidence: 99%

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

Zhao¹,

Bernard²,

Wang³

2013

Biodiscovery

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Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors.

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“…[32][33][34] We next repeated the studies with the F19A mutant of the p53 peptide, starting from the same relative orientations as for the wild-type peptide. We assume that the F19A mutation does not affect the electrostatic complementarity of the two partners, 12,35 since this is a hydrophobic to hydrophobic mutation.…”

mentioning

confidence: 99%

Why is F19Ap53 unable to bind MDM2? Simulations suggest crack propagation modulates binding

Dastidar¹,

Lane²,

Verma³

2012

Cell Cycle

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The p53-MDM2/MDMX axis – A chemotype perspective

Cited by 67 publications

References 63 publications

The Fluorescent Two-Hybrid Assay to Screen for Protein–Protein Interaction Inhibitors in Live Cells: Targeting the Interaction of p53 with Mdm2 and Mdm4

The Fluorescent Two-Hybrid Assay to Screen for Protein–Protein Interaction Inhibitors in Live Cells: Targeting the Interaction of p53 with Mdm2 and Mdm4

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

Why is F19Ap53 unable to bind MDM2? Simulations suggest crack propagation modulates binding

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