The past, present and future of potential small-molecule drugs targeting p53-MDM2/MDMX for cancer therapy

Liu, Yao; Wang, Xiaohui; Wang, Guan; Yang, Yu‐Shang; Yuan, Yong; Ouyang, Liang

doi:10.1016/j.ejmech.2019.05.018

Cited by 89 publications

(87 citation statements)

References 76 publications

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“…The MDM2/MDMX-p53 circuitry plays a pivotal role in cancer cell proliferation, cell cycle progression, apoptosis, and senescence (Karni-Schmidt et al, 2016;Wang et al, 2019b), while USP7 is a critical regulator of this circuitry and tightly controls the stabilities of these proteins, thereby contributing to cancer initiation, progression, and metastasis (Bhattacharya et al, 2018;Rawat et al, 2019). Many MDM2/MDMX inhibitors have been developed for cancer therapy Wang et al, 2018aWang et al, ,b, 2019bde Oliveira Ribeiro et al, 2020), and some of them are in clinical trials (Liu et al, 2019b;Rafal et al, 2019). Most of the MDM2/MDMX inhibitors are designed to target the MDM2/p53 and MDMX/p53 interactions, and wildtype p53 is critical for their anticancer activity (Liu et al, 2019b;Rafal et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Many MDM2/MDMX inhibitors have been developed for cancer therapy Wang et al, 2018aWang et al, ,b, 2019bde Oliveira Ribeiro et al, 2020), and some of them are in clinical trials (Liu et al, 2019b;Rafal et al, 2019). Most of the MDM2/MDMX inhibitors are designed to target the MDM2/p53 and MDMX/p53 interactions, and wildtype p53 is critical for their anticancer activity (Liu et al, 2019b;Rafal et al, 2019). However, p53 mutation and inactivation and MDM2/MDMX overexpression and amplification are frequently observed in various types of human cancer, and the current MDM2/MDMX inhibitors have low or no efficacy in patients with these cancers (Bohlman and Manfredi, 2014;Wang et al, 2014a,b).…”

Section: Discussionmentioning

confidence: 99%

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Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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“…The transcription factor and tumor suppressor p53 is closely related to DNA repair, cellular stress response, and cell cycle control [11,12]. In response to cellular stress signals, the tumor suppressor p53 activates a large number of genes responsible for cell cycle regulation, DNA repair, and apoptosis [13,14].…”

Section: Introductionmentioning

confidence: 99%

ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis

Zhang

Song

et al. 2020

Disease Markers

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Aim. This study was aimed at identifying the role of zinc finger protein 143 (ZNF143) in gastric cancer (GC) progression. Methods. The impact of ZNF143 on the proliferation ability and apoptosis of GC cells was detected. The expression of ZNF143 and related targeted genes was determined using Western blot analysis. The reactive oxygen species (ROS) level of GC cells was examined using the ROS generation assay. The role of ZNF143 in the proliferation of GC cells in vivo was examined using tumor xenograft assay. Results. The ectopic overexpression of ZNF143 promoted the proliferation of GC cells, while its knockdown reduced the effect in vitro. The downregulation of ZNF143 facilitated cell apoptosis. ZNF143 decreased the ROS level in GC cells, resulting in the reduction of cell apoptosis. Transfection with p53 reversed the antiapoptotic effect of ZNF143, while pifithrin-α, a specific inhibitor of p53, reduced the apoptosis in ZNF143-knockdown GC cells. However, p53 had no influence on the ROS level in GC cells. p53 played a key role in inhibiting ROS generation in GC cells, thereby inhibiting apoptosis. The transplanted tumor weight and volume were higher in the ZNF143-overexpressed group than in the ZNF143-knockdown group in vivo. The expression of ZNF143 in the transplanted tumor correlated positively with the proliferation index of Ki67 and negatively with the expression of p53 and cell apoptosis. Conclusion. ZNF143, as a tumor oncogene, promoted the proliferation of GC cells both in vitro and in vivo, indicating that ZNF143 might function as a novel target for GC therapy.

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“…The mouse/murine protein, MDM2, a promising target for developing anti-cancer therapies, is an important negative regulator of the p53 tumor suppressor protein [3,4]. Under normal conditions, the MDM2 protein binds to the transactivation domain of p53, preventing its binding to DNA and labelling blocking the MDM2/p53 interaction may induce apoptosis in both MDM2-overexpressing and wildtype tumor cell lines [11]. Hence, small molecules designed to block the MDM2/p53 interaction can lead to an increase in the level of p53 and its transcriptional activation [3].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antitumor Evaluation, Molecular Modeling and Quantitative Structure–Activity Relationship (QSAR) of Novel 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(1H-benzo[d]imidazol-2(3H)-ylidene)Benzenesulfonamides

Tomorowicz

Sławiński

Żołnowska

et al. 2020

IJMS

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A series of novel 2-[(4-amino-6-R2-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(5-R1-1H-benzo[d]imidazol-2(3H)-ylidene)benzenesulfonamides 6–49 was synthesized by the reaction of 5-substituted ethyl 2-{5-R1-2-[N-(5-chloro-1H-benzo[d]imidazol-2(3H)-ylidene)sulfamoyl]-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds, 22 and 46, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC50: 7–11 µM; 15–24 µM and 11–18 µM), respectively. Further QSAR (Quantitative Structure–Activity Relationships) studies on the cytotoxic activity of investigated compounds toward HCT-116, MCF-7 and HeLa were performed by using different topological (2D) and conformational (3D) molecular descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies allowed us to make three statistically significant and predictive models for them. Moreover, the molecular docking studies were carried out to evaluate the possible binding mode of the most active compounds, 22 and 46, within the active site of the MDM2 protein.

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The past, present and future of potential small-molecule drugs targeting p53-MDM2/MDMX for cancer therapy

Cited by 89 publications

References 76 publications

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis

Synthesis, Antitumor Evaluation, Molecular Modeling and Quantitative Structure–Activity Relationship (QSAR) of Novel 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(1H-benzo[d]imidazol-2(3H)-ylidene)Benzenesulfonamides

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