Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery

Popowicz, Grzegorz M.; Czarna, Anna; Wolf, Siglinde; Wang, Kan; Wang, Wei; Dömling, Alexander; Holak, Tad A.

doi:10.4161/cc.9.6.10956

Cited by 219 publications

(238 citation statements)

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“…For example, inactivation of tumor suppressor p53 has been implicated in various cancers, and one mechanism of inactivation is the inappropriate interaction with the E3 ubiquitin ligase MDM2, leading to excessive degradation of p53 (21). Disruption of this interaction by small molecule inhibitors has shown promise as a potential tool for cancer treatment (21)(22)(23)(24)(25). Current work has illustrated how generating protein interaction networks of protein complexes and profiling the interaction differences between normal and disease states would be greatly beneficial for identifying potential molecular targets for mechanism-driven drug discovery.…”

mentioning

confidence: 99%

Profiling of Protein Interaction Networks of Protein Complexes Using Affinity Purification and Quantitative Mass Spectrometry

Kaake

Wang

Huang

2010

Molecular & Cellular Proteomics

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Protein-protein interactions are important for nearly all biological processes, and it is known that aberrant protein-protein interactions can lead to human disease and cancer. Recent evidence has suggested that protein interaction interfaces describe a new class of attractive targets for drug development. Full characterization of protein interaction networks of protein complexes and their dynamics in response to various cellular cues will provide essential information for us to understand how protein complexes work together in cells to maintain cell viability and normal homeostasis. Affinity purification coupled with quantitative mass spectrometry has become the primary method for studying in vivo protein interactions of protein complexes and whole organism proteomes. Recent developments in sample preparation and affinity purification strategies allow the capture, identification, and quantification of protein interactions of protein complexes that are stable, dynamic, transient, and/or weak. Essential biological processes in cells such as DNA replication, transcription, translation, protein degradation, and cell cycle control are carried out by an assembly of protein molecules that interact and form multisubunit protein complexes (1-5). These macromolecular complexes are important cellular machineries that work hand in hand to maintain normal cell homeostasis. Although the function of each individual subunit is important, the function of the complex as a whole is not simply the sum of its individual components (6 -8). Traditional biochemical methods focus on characterizing a single protein.Although still valid and useful, these methods cannot account for the complexity of macromolecular protein machines. Recently, technological developments in mass spectrometrybased proteomics approaches have made comprehensive characterization of protein complexes possible by enabling the determination of dynamic protein complex compositions, stoichiometries, posttranslational modifications, assemblies, structures, and protein interaction networks (8 -17). This review will report the advances in the study of protein-protein interactions by mass spectrometry.Protein-protein interactions are important for nearly all biological processes, and it is known that aberrant protein-protein interactions can lead to human disease and cancer (18 -20). Sufficient evidence has demonstrated that modulation of protein-protein binding represents an emerging therapeutic paradigm, and protein interaction interfaces describe a new class of attractive targets for drug development. For example, inactivation of tumor suppressor p53 has been implicated in various cancers, and one mechanism of inactivation is the inappropriate interaction with the E3 ubiquitin ligase MDM2, leading to excessive degradation of p53 (21). Disruption of this interaction by small molecule inhibitors has shown promise as a potential tool for cancer treatment (21-25). Current work has illustrated how generating protein interaction networks of protein complexes and profiling t...

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confidence: 99%

Profiling of Protein Interaction Networks of Protein Complexes Using Affinity Purification and Quantitative Mass Spectrometry

Kaake

Wang

Huang

2010

Molecular & Cellular Proteomics

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“…The crystal structures of the resulting compounds MI-63 and MDM2 were recently reported by Popowicz et al [8]. Interestingly, the MI-63 binding pattern is mirrored as previously assumed [9][10][11].…”

Section: Introductionmentioning

confidence: 57%

“…Salicylaldehyde or substituted salicylaldehyde(1-2) and ethyl acetoacetate formed cyclization in the piperidine-catalyzed system to get acetyl coumarin compounds (6-7), And then reacted with isatin (3-5) and glycine or sarcosine [2 + 3] cyclization to form spiro intermediate (8)(9)(10)(11)(12)(13), Wherein the pyrrole 1'-methylated product (8)(9)(10) is directly reacted with the corresponding nitrogen-containing fragment to form (14-18); the remaining intermediates (11-13) are reacted with triphosgene and the corresponding amine to give the 4-methoxybenzyl protected intermediate (19)(20)(21)(22)(23)(24), which is present in the presence of trifluoromethanesulfonic acid deprotection to get 25-30, and finally reacts with the corresponding nitrogen-containing heterocycle and fragment to yield the target product 31-43.…”

Section: Chemistrymentioning

confidence: 99%

“…Wang and his team members used computer-assisted drug screening to find compounds that mimic the indole ring and found that the structural properties of 2-indolinone were most consistent with that of indole. 6-chloro-2-indolinone was identified as a predominant fragment on the basis of previous work on peptide compounds [6,7] and Nutlin (Trp pocket with key chlorine atoms capable of occupying MDM2 protein) [8].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

Liang¹,

Tong²,

Yu³

et al. 2017

Med chem

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A series of spiro-indolin-2-one derivatives were designed and synthesized as p53-MDM2 binding inhibitors. Though p53-MDM2 binding inhibitory and activities against p53 wild-type cell lines of most compounds were not that promising, some obtained structures showed moderate to strong inhibitory activities (IC 50 <0.08 µM) against p53 mutant cell lines (SW620), suggesting that these compounds may have different modes of action to p53 pathway, further studies on treatment of p53 mutant tumors are under investigation.cc

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“…MiRNA participates in various physiological and pathological processes for regulating gene expression and affecting cell proliferation and apoptosis (Farazi et al, 2011). MDM2 is overexpressed in various cancers such as cancers of the prostate, blood, breast, and colon (Popowicz et al, 2010;Wade et al, 2010;Rew and Sun, 2014). MDM2 is closely associated with the pathogenesis and progression of prostate cancer as it can transform cells in the prostate for the generation of xenograft tumors (Ma et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of invasion and migration of prostate cancer cells by miRNA-509-5p via targeting MDM2

Tian

Luo

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Prostate cancer is a common malignancy of the male reproductive-urinary system. MDM2 is an oncogene, whose expression can be regulated by microRNA (miRNA). The present study investigated the expression and correlation of miRNA-509-5p and MDM2 to determine the mechanism of their function in invasion and migration of prostate cancer cells. RT-PCR was performed to detect the expression of miRNA-509-5p and MDM2 in tumor, tumor-adjacent, and normal tissues, obtained from prostate cancer patients, using the HGC-27 cell line as an in vitro model. Cultured HGC-27 cells were transfected with miRNA-509-5p mimics, miRNA-509-5p inhibitor, and mimic control. Expression levels of miRNA-509-5p and MDM2 were quantified by RT-PCR. Cell proliferation and invasion/migration were examined by the MTT and transwell assays, respectively. MiRNA-509-5p was 2 X.M. Tian et al. Genetics and Molecular Research 16 (1): gmr16019195significantly down-regulated in prostate cancer cells exhibiting high MDM2 mRNA levels. MiRNA mimic transfection elevated miRNA levels and suppressed MDM2 expression. With prolonged incubation time, the proliferation ratio and OD values of miRNA-509-5p mimic transfected cells decreased, along with decrease in cell migration and invasion. These results suggested that miRNA-509-5p negatively regulates MDM2 expression via targeting the 3'-UTR of genes. As a novel tumor suppressor, miRNA-509-5p in prostate cancer HGC-27 cells can suppress MDM2 expression and inhibit cell proliferation, invasion, and migration. Therefore, miRNA-509-5p could be used as a novel therapeutic agent in the treatment of prostate cancer.

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Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery

Cited by 219 publications

References 40 publications

Profiling of Protein Interaction Networks of Protein Complexes Using Affinity Purification and Quantitative Mass Spectrometry

Profiling of Protein Interaction Networks of Protein Complexes Using Affinity Purification and Quantitative Mass Spectrometry

Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

Inhibition of invasion and migration of prostate cancer cells by miRNA-509-5p via targeting MDM2

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