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  1,4,5-Trisubstituted Imidazole-Based p53-MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers

Twarda-Clapa, A., Krzanik, S., Kubica, K., Guzik, K., Labuzek, B., Neochoritis, C. G., et al. (2017). 1,4,5-Trisubstituted Imidazole-Based p53-MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers. Journal of Medicinal Chemistry, 60(10), 4234-4244. doi:10.1021/acs.jmedchem.7b00104.

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Twarda-Clapa, Aleksandra1, Author
Krzanik, Sylwia1, Author
Kubica, Katarzyna1, Author
Guzik, Katarzyna1, Author
Labuzek, Beata1, Author
Neochoritis, Constantinos G.1, Author
Khoury, Kareem1, Author
Kowalska, Kaja2, Author              
Czub, Miroslawa1, Author
Dubin, Grzegorz1, Author
Domling, Alexander1, Author
Skalniak, Lukasz1, Author
Holak, Tad A.2, Author              
Affiliations:
1external, ou_persistent22              
2Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              

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Free keywords: SMALL-MOLECULE INHIBITORS; STRUCTURE-BASED DESIGN; PROTEIN-PROTEIN INTERACTIONS; P53 PATHWAY; DRUG DISCOVERY; MDM2-P53 INTERACTION; NMR-SPECTROSCOPY; CANCER-THERAPY; IN-VIVO; MDMXPharmacology & Pharmacy;
 Abstract: The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TPS3 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.

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Language(s): eng - English
 Dates: 2017-05-082017
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Journal of Medicinal Chemistry
Source Genre: Journal
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Publ. Info: Washington DC : ACS Publications
Pages: - Volume / Issue: 60 (10) Sequence Number: - Start / End Page: 4234 - 4244 Identifier: ISSN: 0022-2623
CoNE: https://pure.mpg.de/cone/journals/resource/110992357271168