Isoindolinone-based inhibitors of the MDM2–p53 protein–protein interaction

Hardcastle, Ian R.; Ahmed, Shafiq U.; Atkins, Helen S.; Calvert, A. H.; Curtin, Nicola J.; Farnie, Gillian; Golding, Bernard T.; Griffin, Roger J.; Guyenne, Sabrina; Hutton, Claire; Källblad, Per; Kemp, Stuart J.; Kitching, Martin S.; Newell, David R.; Norbedo, Stefania; Northen, Julian S.; Reid, R. J.; Saravanan, Kappusamy; Willems, Henriëtte M. G.; Lunec, John

doi:10.1016/j.bmcl.2004.12.061

Cited by 90 publications

(52 citation statements)

References 17 publications

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“…In 2005, researchers from University of Newcastle reported the design of MDM2 inhibitors based on the isoindolinone scaffold [68]. 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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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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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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“…MDM2 has emerged as a master regulator of p53 via an autoregulatory feedback loop (Fig. 1) in which both proteins mutually control their cellular concentrations [1][2][3][4][5][6][7][8][10][11][12][13][14][15][16][17][18][19]. Transcription of the mdm2 gene is controlled by p53 under both normal and stressful conditons; therefore, levels of MDM2 rise as p53 is activated and stabilized.…”

Section: The P53 Pathwaymentioning

confidence: 99%

“…Elevated MDM2 then regulates p53 protein activity in three ways: 1) by physically binding to the N-terminal domain of p53 and blocking its transcriptional activity, 2) by inducing nuclear export and 3) by stimulating the degradation of p53 by the E3 ubiquitin ligase/proteasome pathway. Thus, both p53 and MDM2 are maintained at low levels [1][2][3][4][5][6][7][8][10][11][12][13][14][15][16][17][18][19].…”

Section: The P53 Pathwaymentioning

confidence: 99%

“…Referred to as the 'guardian of the genome', dysfunction of p53 by mutations or deletions in the mutational 'hot spot', such as the TP53 gene, disables the tumor suppressing ability of p53 and results in the development of cancer [1][2][3][4][5][6][7][8][10][11][12][13][14][15][16]. Indeed, 50% of all human tumors have a mutated or deleted form of this gene in the DNA-binding domain of p53.…”

mentioning

confidence: 99%

“…The human isoform (HDM2 -used interchangeably in this text), is overex-pressed in a number of human cancers, and is correlated with accelerated cancer progression. Therefore, disrupting the p53-MDM2 PPI, by antagonizing MDM2 and restoring p53 function has been proposed as an approach for the treatment of cancer [1][2][3][4][5][6][7][8][10][11][12][13][14][15][16].…”

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confidence: 99%

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Small Molecule Protein-Protein Inhibitors for the p53-MDM2 Interaction

Dudkina

Lindsley²

2007

CTMC

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This article describes recent progress in the development of small molecule protein-protein inhibitors of the p53-MDM2 (purine double minute 2, or HDM2 for the human congener) protein-protein interaction, with special attention to the diversity of chemotypes reported to disrupt this protein-protein interaction. In >50% of all human cancers, the tumor suppressor 53 KDa phospho-protein p53 is either mutated or deleted. The discovery that MDM2 (HDM2) negatively regulates p53 and therefore inhibits the tumor-suppressor activity of p53 has instigated numerous drug discovery campaigns aimed at disrupting this protein-protein interaction as a potential cancer therapy. Once regarded as intractable targets disrupted by only large macromolecules, protein-protein interactions (PPI) are now mainstream targets due in large part to the intensive effort applied to the study of p53 and the surprising diversity of small molecules (peptides, natural products, terphenyl and other alpha-helix mimetics, chalcones, piperidines, piperazines, fused indoles, isoindolinones, spiro-oxindoles, cis-imidazolines (nutlins), quinolinol and benzodiazepines) capable of disrupting the p53-HDM2 PPI. In addition, drug discovery researchers have employed a number of screening approaches and technologies to identify SMPPIs of the p53-HDM2 interaction, and these discovery paradigms will be discussed. This review will detail the biology of the p53-MDM2 interaction, the major classes of SMPPIs and key medicinal chemistry and in vitro/in vivo biological data reported through October 2006.

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Protein–Protein Interactions as Drug Discovery Targets

Dömling

2010

Burger's Medicinal Chemistry and Drug Discovery

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Protein–protein interactions (PPIs) recently have been recognized as a major class of drug targets. Many of the successful “classical” biotechnology protein drugs are agonists or antagonists of PPIs and there are established pathways for their development. However, small molecular weight compounds as antagonists of PPIs still pose a major problem to discovery due to the inherent physicochemical properties of their targets. Recently, several small molecular weight antagonists of PPIs advanced into clinical trials and thus comprise a proof‐of‐concept to this young area in medicinal chemistry. This chapter summarizes the area of small molecular weight antagonists of PPIs with a focus on recent success stories. After a short introduction into the structural biology of PPIs, recognized important PPI targets, discovery pathways of their inhibitors are discussed. The PPI p53‐Mdm2 with potential applications in cancer is used as a case study to demonstrate to diversity of approaches leading to many different lead structures. In contrast, the discovery of IL‐2/IL‐2 rec. antagonists is discussed to highlight adaptive high affinity binding to hotspot regions.

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Isoindolinone-based inhibitors of the MDM2–p53 protein–protein interaction

Abstract: The design, synthesis and evaluation of 24 isoindolinones as potential inhibitors of the MDM2-p53 interaction is described. The most potent inhibitor NU8231 (ELISA: IC 50 = 5.3 ± 0.9 µM) displays cellular activity in human SJSA cells.

Cited by 90 publications

References 17 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

Small Molecule Protein-Protein Inhibitors for the p53-MDM2 Interaction

Protein–Protein Interactions as Drug Discovery Targets

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