Small-Molecule Inhibitors of the MDM2–p53 Protein–Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment

Zhao, Yujun; Aguilar, Angelo; Bernard, Denzil; Wang, Shaomeng

doi:10.1021/jm501092z

Cited by 392 publications

(323 citation statements)

References 78 publications

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“…In 2004, the identification of Nutlin-3 as the first small molecule inhibitor of MDM2 spurred interest in this approach, which led to the development of several analogous compounds (5). Recent studies have demonstrated the antitumor capacity of small molecule MDM2 inhibitors both in vitro and in vivo, and several of these compounds have advanced to clinical trials (1,6).…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Werner

Huang

Francis

et al. 2015

Molecular Cancer Therapeutics

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MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of gH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/ or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.

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Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Werner

Huang

Francis

et al. 2015

Molecular Cancer Therapeutics

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“…Mdm2 inhibition, which stabilizes p53 levels, is a main therapeutic strategy for treating a number of cancers. Mdm2 inhibitors that ablate Mdm2-p53 interaction are being used in clinical trials for treating cancer; however, the extent to which these drugs affect overall activity of Mdm2 is unclear (66). Based on our findings, such ongoing efforts of Mdm2 inhibition in cancer therapy would benefit by testing the effects of these compounds on cardiac GRK2 expression and βAR signaling.…”

Section: Discussionmentioning

confidence: 80%

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

Jean-Charles¹,

Yu²,

Abraham³

et al. 2017

JCI Insight

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“…Up to seven different inhibitors of MDM2 are currently in early phase I clinical trials (45). Encouragingly, in a number of cases, these compounds have been shown to induce TP53 expression in tumors, induction of apoptosis, and stabilization of disease.…”

Section: Clinical Targeting Of Mutant Tp53mentioning

confidence: 99%

Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis

Corcoran

Clarkson

Stuchbery

et al. 2016

Clinical Cancer Research

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The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair-deficient tumors with drugs that take advantage of the fundamental differences between normal repair-proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132-7. Ó2016 AACR.

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Small-Molecule Inhibitors of the MDM2–p53 Protein–Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment

Cited by 392 publications

References 78 publications

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis

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