Design of Protein–Protein Interaction Inhibitors Based on Protein Epitope Mimetics

Robinson, John A.

doi:10.1002/cbic.200900055

Cited by 29 publications

(12 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activation of wild‐type p53 in human tumors by antagonizing murine d2ouble minute 2 (Mdm2) is a promising and potentially non‐toxic therapeutic strategy (36). The disruption of the p53‐Mdm2 interaction can be accomplished by mimicking the p53 fragment with particular emphasis on the Mdm2‐binding site using peptides, foldamers, and peptoids (α‐helical transactivation domain) (37). However, small‐molecule libraries are favorable for the design of Mdm2 antagonists in terms of the desirable bioavailability and stability (33).…”

Section: Resultsmentioning

confidence: 99%

1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity

et al. 2010

View full text Add to dashboard Cite

1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.

show abstract

Section: Resultsmentioning

confidence: 99%

1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Monomeric GCN4 basic regions do not bind to their target DNA half‐site with high affinity because of the entropic cost associated with the folding of the peptide chain into the appropriate α‐helical conformation, but residue grafting is a powerful strategy for obtaining stabilized α‐helices and thus high‐affinity DNA‐binding monomeric GCN4 peptides . In this approach, selected residues that create the desired binding epitope are inserted (grafted) into a stable three‐dimensional peptide scaffold.…”

Section: Dna‐binding Peptidesmentioning

confidence: 99%

Sequence‐Specific DNA Recognition with Designed Peptides

et al. 2017

View full text Add to dashboard Cite

Inspired by natural transcription factors (TFs), researchers have explored the potential of artificial peptides for the recognition of specific DNA sequences, developing increasingly sophisticated systems that not only display excellent DNA binding properties, but also are endowed with new properties not found in their natural counterparts. Here we review some of the developments in the field of artificial peptide‐based DNA binders, focusing on the supramolecular and molecular design aspects of such systems.

show abstract

“…The activation of wild-type p53 in human tumors with small molecules that antagonize Mdm2 appears to be a promising strategy in the treatment of cancer [ 67 ]. The disruption of the p53-Mdm2 interaction is usually accomplished by peptides, foldamers and peptoids ( α -helical transactivation domain), chemical entities aiming mainly to mimic the p53 fragment and the Mdm2-binding site [ 68 ]. Also, the design of small molecules with appropriate physicochemical properties ( i.e.…”

Section: Antagonists Of P53-mdm2 Interactionsmentioning

confidence: 99%

Targeting Oncogenic Protein-Protein Interactions by Diversity Oriented Synthesis and Combinatorial Chemistry Approaches

Tzakos

Fokas

Johannes³

et al. 2011

Molecules

View full text Add to dashboard Cite

We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions.

show abstract

Design of Protein–Protein Interaction Inhibitors Based on Protein Epitope Mimetics

Cited by 29 publications

References 52 publications

1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity

1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity

Sequence‐Specific DNA Recognition with Designed Peptides

Targeting Oncogenic Protein-Protein Interactions by Diversity Oriented Synthesis and Combinatorial Chemistry Approaches

Contact Info

Product

Resources

About