Novel Activators of the Tumour Suppressor p53

Sunder-Plassmann, Nils; Giannis, Athanassios

doi:10.1002/cbic.200400194

Cited by 5 publications

(1 citation statement)

References 22 publications

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“…Here I shall review progress to date on the most advanced PPI drug target in oncology: the interaction between the tumour suppressor protein p53 and its negative regulator, the human double minute-2 (HDM2) oncogene. Several recent reviews on the topic of the p53–HDM2 interaction have been presented (Chene, 2003 ; Zheleva et al., 2003 ; Chene, 2004 ; Fischer and Lane, 2004 ; Lane and Fischer, 2004 ; Sunder-Plassmann and Giannis, 2004 ; Buolamwini et al., 2005 ; Fotouhi and Graves, 2005 ); here I shall put emphasis on the most recent work.…”

Section: Introductionmentioning

confidence: 99%

Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53–HDM2 Protein–Protein Interaction

Fischer

2006

Int J Pept Res Ther

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Modulation of intracellular protein-protein interactions has been -and remains -a challenging goal for the discovery and development of small-molecule therapeutic agents. Progress in the pharmacological targeting and understanding at the molecular level of one such interaction that is relevant to cancer drug research, viz. that between the tumour suppressor protein p53 and its negative regulator HDM2, is reviewed here. The first X-ray crystal structure of a complex between a small peptide from the trans-activation domain of p53 and the N-terminal domain of HDM2 was reported almost 10 years ago. The nature of this interaction, which involves just three residue side chains in the p53 peptide ligand and a compact hydrophobic binding pocket in the HDM2 receptor, together with the attractive concept of reactivating the anti-proliferative functions of p53 in tumour cells, has spurned a great deal of effort aimed at finding drug-like antagonists of this interaction. A variety of approaches, including both structure-guided peptidomimetic and de novo design, as well as high through-put screening campaigns, have provided a wealth of leads that might be turned into actual drugs. There is still some way to go as far as optimisation and preclinical development of such leads is concerned, but it is clear already now that antagonists of the p53-HDM2 protein-protein interaction have a good chance of ultimately being successful in providing a new anti-cancer therapy modality, both in monotherapy and to potentiate the effectiveness of existing chemotherapies.

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Section: Introductionmentioning

confidence: 99%

Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53–HDM2 Protein–Protein Interaction

Fischer

2006

Int J Pept Res Ther

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Eine verhängnisvolle Affäre: die Ubiquitinylierung von Proteinen

2004

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A Fatal Affair: The Ubiquitinylation of Proteins

Biel¹,

Wascholowski²,

Giannis³

2004

Angew Chem Int Ed

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The kiss of death for a protein is to be labeled with ubiquitin (Ub, see picture). The protein can then be recognized and degraded by the 26S proteasome, an important target in drug research, as it regulates the concentration of certain proteins. Recognition by the proteasome is hindered by two novel proteasome inhibitors, ubistatins A und B, which were identified through a chemical genetic approach.

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Novel Activators of the Tumour Suppressor p53

Cited by 5 publications

References 22 publications

Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53–HDM2 Protein–Protein Interaction

Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53–HDM2 Protein–Protein Interaction

Eine verhängnisvolle Affäre: die Ubiquitinylierung von Proteinen

A Fatal Affair: The Ubiquitinylation of Proteins

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