Cover image for Vol. 12 Issue 18

Editorial Board Chairs: Karl-Heinz Altmann, Antonello Mai, Rainer Metternich. Editor: David Peralta

Impact Factor: 3.225

ISI Journal Citation Reports © Ranking: 2016: 17/60 (Chemistry Medicinal); 73/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

October 08, 2011

VIP: Exhaustive Fluorine Scanning toward Potent p53–Mdm2 Antagonists

VIP: Exhaustive Fluorine Scanning toward Potent p53–Mdm2 AntagonistsYijun Huang, Siglinde Wolf, David Koes, Grzegorz M. Popowicz, Carlos J. Camacho, Tad A. Holak, Alexander Dömling*

The increased incidence of cancer poses a rapidly growing problem particularly for aging Western societies. Interrupting the protein–protein interaction (PPI) between the transcription factor p53 and the mdm2 oncogene with small molecules is a novel and promising non-genotoxic approach to cancer treatment resulting in better drugs with fewer side effects.

Alexander Dömling and Carlos Camacho (University of Pittsburgh, USA) recently introduced the freeware ANCHOR.QUERY for the interactive design of small-molecular-weight PPI antagonists ( The software screens a very large chemical space of virtual multi-component reaction products, which can be instantaneously synthesized and undergo a reality check by physical screening. Using this software the team were able to describe several novel scaffolds that effectively disrupt the p53–mdm2 PPI. The current collaborative effort describes an optimization study toward potent mdm2 antagonists of a Ugi backbone by rapidly synthesizing all possible fluorine derivatives. Computational and biophysical studies (NMR, FP, and a co-crystal structure determined by the Holak group) were used to rationalize the small molecule–receptor interactions. Improved compounds from this project are currently undergoing preclinical development in a collaboration between the US National Institutes of Health (NIH) and the University of Pittsburgh with the aim of addressing unmet medical needs.

Received September 8, 2011; published online September 27, 2011, DOI: 10.1002/cmdc.201100428.

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