Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53–MDM2 protein–protein interaction

Zhuang, Chunlin; Miao, Zhenyuan; Zhu, Lingjian; Zhang, Yongqiang; Guo, Zizhao; Yao, Jing; Dong, Guoqiang; Wang, Shengzheng; Liu, Yang; Chen, Hai; Sheng, Chunquan; Zhang, Wannian

doi:10.1016/j.ejmech.2011.09.043

Cited by 25 publications

(12 citation statements)

References 21 publications

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“…The authors were also able to generate the X-ray crystal structure of the antagonists bound to HDM2, which revealed their R-helix mimetic properties. The synthesis of these compounds was achieved by using an Ugi Later in 2011, Sheng, Zhang and co-workers described the synthesis of the thio-benzodiazepines and their biological activity of p53-MDM2 inhibitors [179]. Most compounds had nano/micromolar affinity towards MDM2, and some showed activity similar to that of nutlin-3a.…”

Section: Benzodiazepinone Derivativesmentioning

confidence: 99%

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Recent Synthetic Approaches towards Small Molecule Reactivators of p53

et al. 2020

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The tumor suppressor protein p53 is often called “the genome guardian” and controls the cell cycle and the integrity of DNA, as well as other important cellular functions. Its main function is to trigger the process of apoptosis in tumor cells, and approximately 50% of all cancers are related to the inactivation of the p53 protein through mutations in the TP53 gene. Due to the association of mutant p53 with cancer therapy resistance, different forms of restoration of p53 have been subject of intense research in recent years. In this sense, this review focus on the main currently adopted approaches for activation and reactivation of p53 tumor suppressor function, focusing on the synthetic approaches that are involved in the development and preparation of such small molecules.

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Section: Benzodiazepinone Derivativesmentioning

confidence: 99%

“…Later in 2011, Sheng, Zhang and co-workers described the synthesis of the thio-benzodiazepines and their biological activity of p53-MDM2 inhibitors [179]. Most compounds had nano/micromolar affinity towards MDM2, and some showed activity similar to that of nutlin-3a.…”

Section: Benzodiazepinone Derivativesmentioning

confidence: 99%

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

et al. 2020

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“…2) [229,[297][298][299], were identified via HTS. Structure-based design and molecular modeling were then used for ligand screening and optimization [300][301][302][303][304] leading to in vitro activities down to IC 50 = 3 nM [302]. Several computational techniques have helped designing and screening for ligands of HDM2 or MDM2.…”

Section: Hdm2mentioning

confidence: 99%

Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

Metz¹,

Ciglia²,

Gohlke³

2012

CPD

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During the last decades, a large amount of evidence has been gathered on the importance of protein-protein interactions in tuning and regulating most important biological processes. Since many of these pathways are deeply involved in diseases, extensive research efforts have been undertaken towards the modulation of protein-protein interactions. At the early stage of this challenge most of the attention was drawn to the drawbacks of such a therapeutic approach. Encouragingly, however, several recent studies provided a proof of concept that protein-protein interactions are actually valuable targets and that they do have a promising therapeutic potential. This review is divided into three sections. In the first section we summarize the general features of protein-protein interfaces, focusing on the characteristics that make them different from classical protein-ligand binding sites, as well as on problematic aspects that hamper the application of classical drug discovery approaches. In the second section, we present how some of the characteristics of protein-protein interactions can be exploited fruitfully in drug design, hence focusing on the druggability of protein-protein interfaces. Methods successfully applied to protein-protein interactions will be introduced, giving special attention to the computational ones. In the third section, three case studies are presented. First, we describe protein-protein interaction modulators targeting HDM2 and the computational methods applied to identify them. Next, we present the retrospective application of the discussed approaches on the well-examined target IL-2. We conclude with a prospective application to the NHR2 protein, a target just recently validated experimentally with the aid of computational methods.

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“…Structure-based design has also led to the development of several other molecules that target MDM2's hydrophobic cleft using various chemical scaffolds, such as methylbenzo-amines (Dudgeon et al, 2010), imidazole-indoles (Czarna et al, 2010), isoindolinones (Hardcastle et al, 2006; Hardcastle et al, 2011; Riedinger et al, 2011), pyrrolopyrimidines (Lee et al, 2011), sulphonamides (Galatin & Abraham, 2004), and benzodiazepines (Z. Yu et al, 2014; Zhuang et al, 2011), which all demonstrate nanomolar binding affinities to MDM2 and with one pyrrolidinone exhibiting dual MDM2/MDMX activity (Zhuang et al, 2012) and one pyrrolopyrazole seemingly active against both MDM2 and the NF-κB complex (Zhuang et al, 2014), a different cancer-related pathway (DiDonato, Mercurio, & Karin, 2012). Perhaps most promising are a series of piperidonones (AM-8553, AM-7209, AMG 232) and morpholinones (AM-8735) developed from Amgen laboratories that exhibit exceptional pharmacokinetic properties, such as low clearance rate, long half-life, and high oral bioavailability (Gonzalez-Lopez de Turiso et al, 2013; Gonzalez, Eksterowicz, et al, 2014; Rew et al, 2012; Rew et al, 2014; Sun et al, 2014).…”

Section: Small Molecule Wild-type P53 Activatorsmentioning

confidence: 99%

Reviving the guardian of the genome: Small molecule activators of p53

Nguyen

Liao

Zeng

et al. 2017

Pharmacology & Therapeutics

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The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

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Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53–MDM2 protein–protein interaction

Cited by 25 publications

References 21 publications

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

Reviving the guardian of the genome: Small molecule activators of p53

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