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  Discovery of Highly Potent p53-MDM2 Antagonists and Structural Basis for Anti-Acute Myeloid Leukemia Activities

Huang, Y., Wolf, S., Beck, B., Koehler, L.-M., Khoury, K., Popowicz, G. M., et al. (2014). Discovery of Highly Potent p53-MDM2 Antagonists and Structural Basis for Anti-Acute Myeloid Leukemia Activities. ACS CHEMICAL BIOLOGY, 9(3), 802-811. doi:10.1021/cb400728e.

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 Creators:
Huang, Yijun1, Author
Wolf, Siglinde2, Author              
Beck, Barbara1, Author
Koehler, Lisa-Maria1, Author
Khoury, Kareem1, Author
Popowicz, Grzegorz M.2, Author              
Goda, Sayed K.1, Author
Subklewe, Marion1, Author
Twarda, Aleksandra1, Author
Holak, Tad2, Author              
Domling, Alexander1, 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: PROTEIN-PROTEIN INTERACTIONS; LEAD COMPOUNDS; CELL-LINES; P53; MDM2; NMR; INHIBITORS
 Abstract: The inhibition of p53-MDM2 interaction is a promising new approach to non-genotoxic cancer treatment. A potential application for drugs blocking the p53-MDM2 interaction is acute myeloid leukemia (AML) due to the occurrence of wild type p53 (wt p53) in the majority of patients. Although there are very promising preclinical results of several p53-MDM2 antagonists in early development, none of the compounds have yet proven the utility as a next generation anticancer agent. Herein we report the design, synthesis and optimization of YH239-EE (ethyl ester of the free carboxylic acid compound YH239), a potent p53-MDM2 antagonizing and apoptosis-inducing agent characterized by a number of leukemia cell lines as well as patient-derived AML blast samples. The structural basis of the interaction between MDM2 (the p53 receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a prodrug and is the most potent compound that induces apoptosis in AML cells and patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further investigation and progression of YH239-EE.

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Language(s): eng - English
 Dates: 2014-03
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000333477300028
DOI: 10.1021/cb400728e
 Degree: -

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Title: ACS CHEMICAL BIOLOGY
Source Genre: Journal
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Publ. Info: 1155 16TH ST, NW, WASHINGTON, DC 20036 USA : AMER CHEMICAL SOC
Pages: - Volume / Issue: 9 (3) Sequence Number: - Start / End Page: 802 - 811 Identifier: ISSN: 1554-8929