Retraction of “Efficient Reactivation of p53 in Cancer Cells by a Dual MdmX/Mdm2 Inhibitor”

Qin, Lingyun; Yang, Fei; Zhou, Cindy Ke; Chen, Yao; Zhang, Hua‐Shan; Su, Zhengding

doi:10.1021/jacs.5b11033

Cited by 4 publications

(5 citation statements)

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“…However, the paper that reported H109 was retracted due to unauthorized use of crystal structures of MDM2/Nutlin-3a complexes. 87 In addition, 24 (Figure 11) was found to interrupt native MDM4/p53 and MDM2/p53 interaction with inhibitory IC 50 values of 77.4 and 72.0 nM, respectively, in SHSY-5Y and U87MG cell lysate-based screening assays. 88 However, there is little experimental evidence to support that 24 binds to MDM4 on the N-terminal p53 binding domain.…”

Section: Small-molecule Inhibitors That Block Mdm4-p53 Protein−protei...mentioning

confidence: 97%

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Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Zhang

Lou

et al. 2021

J. Med. Chem.

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MDM4 is a homologue of MDM2, serving cooperatively as the negative regulator of tumor suppressor p53. Under the shadow of MDM2 inhibitors, limited efforts had been put into the discovery of MDM4 modulators. Recent studies of the experimental drug ALRN-6924, a dual MDM4 and MDM2 inhibitor, suggest that concurrent inhibition of MDM4 and MDM2 might be beneficial over only MDM2 inhibition. In view of the present research progress, we summarized published inhibitors of MDM4/p53 interactions including both peptide-based compounds and small molecules. Cocrystal structures of ligand/ MDM4 complexes have been examined, and their structural features were compiled and compared in order to show the molecular basis required for high MDM4 binding affinities. Representative examples of small-molecule MDM4 inhibitors were discussed, followed by clinical results of ALRN-6924, together, providing a consolidated reference for further development of MDM4 inhibitors, either dual or selective.

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Section: Small-molecule Inhibitors That Block Mdm4-p53 Protein−protei...mentioning

confidence: 97%

“…H109 also induces the expression of p21 gene but not p53 gene in HCT116, RKO, and H460a cancer cells. However, the paper that reported H109 was retracted due to unauthorized use of crystal structures of MDM2/Nutlin-3a complexes …”

Section: Small-molecule Inhibitors That Block Mdm4-p53 Protein–protei...mentioning

confidence: 99%

Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Zhang

Lou

et al. 2021

J. Med. Chem.

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“…27,40 Recently, H109 and 10 were reported as potent dual inhibitors of MDM2/ 4, with H109 exerting cellular activity in the μM range. 27,48,49 In addition, RO-5963 blocked MDM2/4 and p53 interactions with low nM IC 50 values and showed robust cellular antitumor activity. 40 Interestingly, structural biology studies show that RO-5963 induced MDM4 dimerization.…”

Section: ■ Introductionmentioning

confidence: 98%

“…The p53-binding domains of MDM2 and MDM4 share similar peptide sequences and three-dimensional structures (Figure ). , To concurrently block MDM2/p53 and MDM4/p53 interactions, several peptide-based dual inhibitors have been reported, ,,,, while small molecules that simultaneously bind to MDM2/4 with high affinities (MDM2/4 dual inhibitors) are still limited. − ,, For example, 8 and 9 have low nM binding IC 50 values to MDM2, while they have a μM to sub-μM range when binding to MDM4. , Recently, H109 and 10 were reported as potent dual inhibitors of MDM2/4, with H109 exerting cellular activity in the μM range. ,, In addition, RO-5963 blocked MDM2/4 and p53 interactions with low nM IC 50 values and showed robust cellular antitumor activity . Interestingly, structural biology studies show that RO-5963 induced MDM4 dimerization.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells

Zhang

Yan

et al. 2022

J. Med. Chem.

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Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding K i values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.

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“…Thus, MDM2 may promote tumor occurrence and development by promoting tumor cell proliferation and growth. It is an oncogene that can promote tumor occurrence and development [13,14]. MDM2 can play a role in 2 ways, as its translation product can bind with p53 protein, thus inhibiting pP53 transcription activity.…”

Section: Introductionmentioning

confidence: 99%

P53 and Murine Double Mimute 2 (MDM2) Expression Changes and Significance in Different Types of Endometrial Lesions

Jiang

Dan

et al. 2016

Med Sci Monit

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BackgroundEndometrial lesions are common in obstetrics and gynecology, including endometrial polyps, uterine adenomyosis, and malignant endometrial adenocarcinoma. Endometrial lesions seriously affect women’s health, fertility, quality of life, and life safety. As a pro-apoptosis gene, p53 is considered to be closely related with human tumors. Murine double mimute 2 (MDM2) is an oncogene that can promote tumor occurrence and development. P53 and MDM2 expression and significance in different types of endometrial lesions have not been fully elucidated.Material/MethodsNormal endometrium, endometrial polyps, uterine adenomyosis, and endometrial adenocarcinoma tissue samples were collected. Real-time PCR was used to detect p53 and MDM2 mRNA expression. Immunohistochemical staining and Western blot analysis were applied to test p53 and MDM2 protein expression. Their correlation with clinical staging of endometrial adenocarcinoma was analyzed.ResultsP53 and MDM2 mRNA and protein expression were significantly elevated in the endometrial polyps group and the endometrial adenocarcinoma group compared with the normal control group (P<0.05). Their levels increased more obviously in endometrial adenocarcinoma compared with endometrial polyps (P<0.05). P53 and MDM2 mRNA and protein expression were slightly enhanced in uterine adenomyosis compared with normal controls, but this difference lacked statistical significance (P>0.05). P53 and MDM2 mRNA and protein level showed a positive correlation. Significantly higher expression of p53 or MDM2 was observed in patients with stage III compared to those in patients with stage II. Higher expression was also observed in patients with stage II than in patients with stage I.ConclusionsP53 and MDM2 mRNA and protein were elevated in endometrial polyps and endometrial adenocarcinoma and their expressions were correlated with clinical staging of endometrial adenocarcinoma. They can promote cancer occurrence and development, and can be treated to assist diagnosis and provide a reference for treatment.

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Retraction of “Efficient Reactivation of p53 in Cancer Cells by a Dual MdmX/Mdm2 Inhibitor”

Cited by 4 publications

References 0 publications

Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells

P53 and Murine Double Mimute 2 (MDM2) Expression Changes and Significance in Different Types of Endometrial Lesions

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