Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein−Protein Interaction: Structure−Activity Studies Leading to Improved Potency

Hardcastle, Ian R.; Liu, Junfeng; Valeur, Eric; Watson, Anna; Ahmed, Shafiq U.; Blackburn, Timothy J.; Bennaceur, K.; Clegg, William; Drummond, Catherine J.; Endicott, Jane; Golding, Bernard T.; Griffin, Roger J.; Gruber, Jan; Haggerty, Karen; Harrington, Ross W.; Hutton, Claire; Kemp, Stuart J.; Lü, Xiaohong; McDonnell, James M.; Newell, David R.; Noble, M.E.M.; Payne, Sara L.; Revill, Charlotte; Riedinger, Christiane; Xu, Qing; Lunec, John

doi:10.1021/jm1011929

Cited by 128 publications

(75 citation statements)

References 27 publications

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“…The same group also developed a series of diastereomeric spiro-oxindoles such as MI888 which is a potent MDM2 inhibitor (Ki =0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy [366]. Simultaneously, other drugs that have been reported so far include pyrazole and imidazole compounds [367], imidazole-indoles [368], isoindolinones [369] pyrrolidinones such as PXN822 [370,371], piperidines [372], spirooxindoles [373] and the sulphonamide NSC279287 [374]. …”

Section: Small Molecule Activators Of P53 Pathwaymentioning

confidence: 99%

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

et al. 2014

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Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism.

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Section: Small Molecule Activators Of P53 Pathwaymentioning

confidence: 99%

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

et al. 2014

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“…In addition, dose-dependent Small-molecule MDM2 and MDMX inhibitors activation of p53 was achieved by treatment of 21 in a range of 5-40 µM in a luciferase-based, p53-dependent reporter gene assay. Subsequently, a structure-based optimization was performed to improve the binding affinity to MDM2 and cellular potency for this class of compounds [70].…”

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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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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“…Both classes of antagonists have also been demonstrated to have in vivo activity [6, 8]. The first of this class of compound, RG7112 (Roche) has recently completed phase I clinical trials [9], whilst others, such as the spirooxindoles and the isoindolinones, which are being developed in this laboratory [10], are in late stage pre-clinical development.…”

Section: Introductionmentioning

confidence: 99%

TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation

et al. 2016

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Non-genotoxic reactivation of the p53 pathway by MDM2-p53 binding antagonists is an attractive treatment strategy for wild-type TP53 cancers. To determine how resistance to MDM2/p53 binding antagonists might develop, SJSA-1 and NGP cells were exposed to growth inhibitory concentrations of chemically distinct MDM2 inhibitors, Nutlin-3 and MI-63, and clonal resistant cell lines generated. The p53 mediated responses of parental and resistant cell lines were compared. In contrast to the parental cell lines, p53 activation by Nutlin-3, MI-63 or ionizing radiation was not observed in either the SJSA-1 or the NGP derived cell lines. An identical TP53 mutation was subsequently identified in both of the SJSA-1 resistant lines, whilst one out of three identified mutations was common to both NGP derived lines. Mutation specific PCR revealed these mutations were present in parental SJSA-1 and NGP cell populations at a low frequency. Despite cross-resistance to a broad panel of MDM2/p53 binding antagonists, these MDM2-amplified and TP53 mutant cell lines remained sensitive to ionizing radiation (IR). These results indicate that MDM2/p53 binding antagonists will select for p53 mutations present in tumours at a low frequency at diagnosis, leading to resistance, but such tumours may nevertheless remain responsive to alternative therapies, including IR.

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Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein−Protein Interaction: Structure−Activity Studies Leading to Improved Potency

Cited by 128 publications

References 27 publications

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

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

TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation

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