Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein−Protein Interaction: Structure−Activity Studies Leading to Improved Potency

2011 ◽  
Vol 54 (5) ◽  
pp. 1233-1243 ◽  
Author(s):  
Ian R. Hardcastle ◽  
Junfeng Liu ◽  
Eric Valeur ◽  
Anna Watson ◽  
Shafiq U. Ahmed ◽  
...  
Keyword(s):  
Protein Interaction ◽  
P53 Protein ◽  
Interaction Structure ◽  
Protein Protein Interaction ◽  
Structure Activity ◽  
Double Minute ◽  
Murine Double Minute

Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

2021 ◽  
Author(s):  
Gianni Chessari ◽  
Ian R. Hardcastle ◽  
Jong Sook Ahn ◽  
Burcu Anil ◽  
Elizabeth Anscombe ◽  
...  
Keyword(s):  
Protein Interaction ◽  
P53 Protein ◽  
Protein Protein Interaction ◽  
Orally Active

MDM2-p53 protein–protein interaction inhibitors: A-ring substituted isoindolinones

2011 ◽  
Author(s):  
Anna F. Watson ◽  
Junfeng Liu ◽  
Karim Bennaceur ◽  
Catherine J. Drummond ◽  
Jane A. Endicott ◽  
...  
Keyword(s):  
Protein Interaction ◽  
P53 Protein ◽  
Protein Protein Interaction

Recent advances in β-catenin/BCL9 protein–protein interaction inhibitors

2021 ◽  
Author(s):  
Hao Zhang ◽  
Ya Bao ◽  
Chenglong Liu ◽  
Jianqi Li ◽  
Di Zhu ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Wnt Pathway ◽  
Biochemical Properties ◽  
Discovery Process ◽  
Protein Protein Interaction ◽  
Promising Strategy ◽  
Structure Activity ◽  
Design Structure ◽  
Direct Targeting ◽  
Normal Embryonic Development

Wnt/β-catenin signaling is crucial both in normal embryonic development and throughout the life of an organism. Moreover, aberrant Wnt signaling has been associated with various diseases, especially cancer and fibrosis. Recent research suggests that direct targeting of the β-catenin/BCL9 protein–protein interaction (PPI) is a promising strategy to block the Wnt pathway. Progress in understanding the cocrystalline complex and mechanism of action of the β-catenin/BCL9 interaction facilitates the discovery process of its inhibitors, but only a few inhibitors have been reported. In this review, the discovery and development of β-catenin/BCL9 PPI inhibitors in the areas of drug design, structure–activity relationships and biological and biochemical properties are summarized. In addition, perspectives for the future development of β-catenin/BCL9 PPI inhibitors are explored.

scholarly journals An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3174 ◽  
Author(s):  
Xin Xue ◽  
Gang Bao ◽  
Hai-Qing Zhang ◽  
Ning-Yi Zhao ◽  
Yuan Sun ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Drug Target ◽  
P53 Protein ◽  
Pharmacophore Model ◽  
Cellular Level ◽  
Complex Structures ◽  
Ligand Complex ◽  
Null Cell ◽  
Protein Protein Interaction ◽  
First Time

: The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of Ki from 102 to 103 nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs.

Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2−Tumor Protein 53 Protein−Protein Interaction

2009 ◽  
Vol 52 (22) ◽  
pp. 7044-7053 ◽  
Author(s):  
John G. Allen ◽  
Matthew P. Bourbeau ◽  
G. Erich Wohlhieter ◽  
Michael D. Bartberger ◽  
Klaus Michelsen ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Protein Interaction ◽  
Mouse Double Minute ◽  
Double Minute

scholarly journals The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth

1993 ◽  
Vol 13 (1) ◽  
pp. 301-306 ◽  
Author(s):  
C A Finlay
Keyword(s):  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Rat Embryo ◽  
Ras Gene ◽  
Double Minute ◽  
Murine Double Minute ◽  
Low Levels ◽  
Wild Type P53 ◽  
P53 Genes

Expression of a p53-associated protein, Mdm-2 (murine double minute-2), can inhibit p53-mediated transactivation. In this study, overexpression of the Mdm-2 protein was found to result in the immortalization of primary rat embryo fibroblasts (REFs) and, in conjunction with an activated ras gene, in the transformation of REFs. The effect of wild-type p53 on the transforming properties of mdm-2 was determined by transfecting REFs with ras, mdm-2, and normal p53 genes. Transfection with ras plus mdm-2 plus wild-type p53 resulted in a 50% reduction in the number of transformed foci (relative to the level for ras plus mdm-2); however, more than half (9 of 17) of the cell lines derived from these foci expressed low levels of a murine p53 protein with the characteristics of a wild-type p53. These results are in contrast to previous studies which demonstrated that even minimal levels of wild-type p53 are not tolerated in cells transformed by ras plus myc, E1A, or mutant p53. The mdm-2 oncogene can overcome the previously demonstrated growth-suppressive properties of p53.

Abstract A140: Identification of substituted isoindolinones as potent inhibitors of the MDM2‐p53 protein‐protein interaction

2009 ◽  
Author(s):  
Anna Watson ◽  
Junfeng Liu ◽  
Elizabeth Armstrong ◽  
Timothy Blackburn ◽  
Jane A. Endicott ◽  
...  
Keyword(s):  
Protein Interaction ◽  
P53 Protein ◽  
Protein Protein Interaction
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