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Cited by 275

The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.

Chalcone Derivatives Antagonize Interactions between the Human Oncoprotein MDM2 and p53

Open access
Stoll, Raphael, Renner, Christian, Hansen, Silke, Palme, Stefan, Klein, Christian, Belling, Anja, Zeslawski, Wojciech, Kamionka, Mariusz, Rehm, Till, Mühlhahn, Peter, Schumacher, Ralf, Hesse, Friederike, Kaluza, Brigitte, Voelter, Wolfgang, Engh, Richard A., Holak, Tad A.·2001·Biochemistry
DOI 10.1021/bi000930v
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Abstract

The oncoprotein MDM2 inhibits the tumor suppressor protein p53 by binding to the p53 transactivation domain. The p53 gene is inactivated in many human tumors either by mutations or by binding to oncogenic proteins. In some tumors, such as soft tissue sarcomas, overexpression of MDM2 inactivates an otherwise intact p53, disabling the genome integrity checkpoint and allowing cell cycle progression of defective cells. Disruption of the MDM2/p53 interaction leads to increased p53 levels and restored p53 transcriptional activity, indicating restoration of the genome integrity check and therapeutic potential for MDM2/p53 binding antagonists. Here, we show by multidimensional NMR spectroscopy that chalcones (1,3-diphenyl-2-propen-1-ones) are MDM2 inhibitors that bind to a subsite of the p53 binding cleft of human MDM2. Biochemical experiments showed that these compounds can disrupt the MDM2/p53 protein complex, releasing p53 from both the p53/MDM2 and DNA-bound p53/MDM2 complexes. These results thus offer a starting basis for structure-based drug design of cancer therapeutics.

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Crossref · 10.1021/bi000930v

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Metadata

Authors
Stoll, R., Renner, C., Hansen, S., Palme, S., Klein, C., Belling, A., Zeslawski, W., Kamionka, M., Rehm, T., Mühlhahn, P., Schumacher, R., Hesse, F., Kaluza, B., Voelter, W., Engh, R. A., & Holak, T. A.
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2000-12-13
Volume
40
Issue
2
Pages
336-344
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi000930v
OpenAlex
W2035177083
Cited by
275
References
11
FWCI
3.51
Type
journal article
Language
en
Open access
green

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