Small-Molecule Inhibitors of the MDM2-p53 Protein−Protein Interaction Based on an Isoindolinone Scaffold

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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“…Guided by computational docking studies, extensive modifications of isoindolinones 18-20 were performed ( Figure 9) [69].…”

Section: Structure-based Design Of Isoindolinones As Mdm2 Inhibitorsmentioning

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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“…86 Weak inhibitors, identified by compound screening via ELISA, were improved based on computationally guided variations in peripheral substituents. One of the most effective compounds was 23 ( Figure 14), which had an IC 50 of 16 lM and which induced expression of p53-dependent genes in a cancer cell line with high MDM2 levels (10-40 lM).…”

Section: Isoindolinonesmentioning

confidence: 99%

Targeting protein–protein interactions: Lessons from p53/MDM2

2007

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The tremendous challenge of inhibiting therapeutically important protein–protein interactions has created the opportunity to extend traditional medicinal chemistry to a new class of targets and to explore nontraditional strategies. Here we review a widely studied system, the interaction between tumor suppressor p53 and its natural antagonist MDM2, for which both traditional and nontraditional approaches have been reported. This system has been a testing ground for novel proteomimetic scaffold‐based strategies, i.e., for attempts to mimic the recognition surface displayed by a folded protein with unnatural oligomers. Retroinverso peptides, peptoids, terphenyls, β‐hairpins, p‐oligobenzamides, β‐peptides, and miniproteins have all been explored as inhibitors of the p53/MDM2 interaction, and we focus on these oligomer‐based efforts. Traditional approaches have been successful as well, and we briefly review small molecule inhibitors along with other strategies for reactivation of the p53 pathway, for comparison with oligomer‐ based approaches. We close with comments on an emerging dichotomy among protein–protein interaction targets. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 657–686, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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“…Furthermore, NSC279287, NSC66811 and terphenyl compounds are small molecules that can also disrupt the MDM2-p53 interaction [50–52]. Additional small molecule inhibitors of the MDM2-p53 interaction have been revealed later on, such as TDP521252, TDP665759, PXN727, PXN822 and isoindolinones, which are currently under pre-clinical development [53–57]. By contrast, the two molecules SJ172550 and XI-006 were recently identified to restore WT p53 activity by targeting MDMX.…”

Section: Introductionmentioning

confidence: 99%

Targeting p53-MDM2-MDMX Loop for Cancer Therapy

Zhang

Zeng

2014

Subcellular Biochemistry

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The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as “the guardian of the genome”, because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the transcriptional targets of p53. On account of the importance of the p53-MDM2- MDMX loop in the initiation and development of wild type p53-containing tumors, intensive studies over the past decade have been aiming to identify small molecules or peptides that could specifically target individual protein molecules of this pathway for developing better anti-cancer therapeutics. In this chapter, we review the approaches for screening and discovering efficient and selective MDM2 inhibitors with emphasis on the most advanced synthetic small molecules that interfere with the p53-MDM2 interaction and are currently on Phase I clinical trials. Other therapeutically useful strategies targeting this loop, which potentially improve the prospects of cancer therapy and prevention, will also be discussed briefly.

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Small-Molecule Inhibitors of the MDM2-p53 Protein−Protein Interaction Based on an Isoindolinone Scaffold

Cited by 128 publications

References 49 publications

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

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

Targeting protein–protein interactions: Lessons from p53/MDM2

Targeting p53-MDM2-MDMX Loop for Cancer Therapy

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