Robust Generation of Lead Compounds for Protein–Protein Interactions by Computational and MCR Chemistry: p53/Hdm2 Antagonists

Czarna, Anna; Beck, Barbara; Srivastava, S. C.; Popowicz, Grzegorz M.; Wolf, Siglinde; Huang, Yijun; Bista, Michal; Holak, Tad A.; Dömling, Alexander

doi:10.1002/anie.201001343

Cited by 130 publications

(107 citation statements)

References 42 publications

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“…Finally, a fragment-based strategy, involving “multicomponent reaction chemistry” (MCR), identified imidazolines as dual MDM2/MDMX inhibitors [91]. The crystal structures of p53-MDM2 (PDB: 1YCR) and imidazole antagonist PB12 bound to MDM2 (PDB: 3LBK) were used as templates to identify a fragmentation/anchor.…”

Section: Discovery Of Inhibitors Targeting the P53-mdm2-mdmx Loopmentioning

confidence: 99%

Targeting p53-MDM2-MDMX Loop for Cancer Therapy

Zhang

Zeng

2014

Subcellular Biochemistry

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The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as “the guardian of the genome”, because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the transcriptional targets of p53. On account of the importance of the p53-MDM2- MDMX loop in the initiation and development of wild type p53-containing tumors, intensive studies over the past decade have been aiming to identify small molecules or peptides that could specifically target individual protein molecules of this pathway for developing better anti-cancer therapeutics. In this chapter, we review the approaches for screening and discovering efficient and selective MDM2 inhibitors with emphasis on the most advanced synthetic small molecules that interfere with the p53-MDM2 interaction and are currently on Phase I clinical trials. Other therapeutically useful strategies targeting this loop, which potentially improve the prospects of cancer therapy and prevention, will also be discussed briefly.

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Section: Discovery Of Inhibitors Targeting the P53-mdm2-mdmx Loopmentioning

confidence: 99%

Targeting p53-MDM2-MDMX Loop for Cancer Therapy

Zhang

Zeng

2014

Subcellular Biochemistry

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“…4c,d Therefore, blocking the interaction between wild-type p53 and its negative regulators MDM2 and MDMX has become an important target in oncology to restore the anti-tumor activity of p53. 5–7 …”

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confidence: 99%

“…17 The starting point for our antagonist discoveries was the anchoring side chain of tryptophan embedded in a deep hydrophobic pocket formed by the residues Leu57, Phe86 and Ile99 using our pharmacophore based virtual screening platform ANCHOR.QUERY. 7,15,18,25 This had led to several scaffolds potently antagonizing p53-MDM2. Amongst them we could also solve representative co-crystal structures of the imidazoloindole derivative 1 binding to MDM2 (PDB ID: 3LBK) and the close relative MDMX (PDB ID: 3LBJ) confirming the initial binding hypothesis.…”

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confidence: 99%

2,3′-Bis(1′H-indole) heterocycles: New p53/MDM2/MDMX antagonists

Neochoritis

Wang

Estrada‐Ortiz

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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The protein-protein interaction of p53 and MDM2/X is a promising non genotoxic anticancer target. A rapid and efficient methodology was developed to synthesize the 2,3'-bis(1'H-indole) heterocyclic scaffold 2 as ester, acid and amide derivatives. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and HSQC experiments, indicating good inhibition and a perfect starting point for further optimizations.

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“…This software was instrumental to the discovery of multiple potent and selective MCR-based antagonists of the protein-protein interaction between p53 and Mdm2 (Figure 2). [33,34] Thus, computational approaches to screen MCR libraries will likely play a more and more important role in the early drug discovery process in the future. An increasing amount of high-resolution structural information on MCR molecules bound to biological receptors is becoming available.…”

Section: Large-scale Pharmacophore-based Virtual Screening Of Mcr Libmentioning

confidence: 99%

Multicomponent Reactions, Union of MCRs and Beyond

Zarganes‐Tzitzikas

Chandgude

Dömling

2015

The Chemical Record

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244

142

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Multicomponent reactions (MCRs), which are located between one- and two-component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted.

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Robust Generation of Lead Compounds for Protein–Protein Interactions by Computational and MCR Chemistry: p53/Hdm2 Antagonists

Cited by 130 publications

References 42 publications

Targeting p53-MDM2-MDMX Loop for Cancer Therapy

Targeting p53-MDM2-MDMX Loop for Cancer Therapy

2,3′-Bis(1′H-indole) heterocycles: New p53/MDM2/MDMX antagonists

Multicomponent Reactions, Union of MCRs and Beyond

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