ABSTRACT
α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.
Subject(s)
Proto-Oncogene Proteins c-mdm2/chemistry , Quantitative Structure-Activity Relationship , Tumor Suppressor Protein p53/chemistry , Dose-Response Relationship, Drug , Humans , Ligands , Models, Molecular , Molecular Structure , Protein Binding/drug effects , Protein Structure, Secondary , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity Relationship , Surface Properties , Tumor Suppressor Protein p53/antagonists & inhibitorsABSTRACT
The development of foldamers capable of selective molecular recognition of solvent exposed protein surfaces represents an outstanding challenge in supramolecular chemical biology. Here we introduce an oligoamide foldamer with well-defined conformation that bears all the hallmarks of an information rich oligomer. Specifically, the foldamer recognizes its target protein hDM2 leading to inhibition of its protein-protein interaction with p53 in a manner that depends upon the composition, spatial projection and stereochemistry of functional groups appended to the scaffold. Most significantly, selective inhibition of p53/hDM2 can be achieved against four other targets and the selectivity for p53/hDM2 inhibition versus Mcl-1/NOXA-B inhibition is critically dependent upon the stereochemistry of the helix mimetic.
ABSTRACT
α-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.
Subject(s)
Proto-Oncogene Proteins c-mdm2/chemistry , Tumor Suppressor Protein p53/chemistry , Amides/chemistry , Biomimetics , Click Chemistry , Humans , Inhibitory Concentration 50 , Myeloid Cell Leukemia Sequence 1 Protein/chemistry , Protein Binding , Protein Interaction Mapping , Protein Structure, Secondary , Proteomics/methods , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Solvents/chemistry , Surface Properties , Tumor Suppressor Protein p53/antagonists & inhibitors , bcl-X Protein/chemistryABSTRACT
Rapid access to rigid rods: A method is described for the synthesis of 3-O-alkylated aromatic oligobenzamide foldamers that could be used for assembly of libraries of α-helix mimetic inhibitors of protein-protein interactions (see scheme; Fmoc=9-fluorenylmethoxycarbonyl).
Subject(s)
Benzamides/chemical synthesis , Chemistry, Organic/methods , Fluorenes/chemistry , Alkylation , Benzamides/chemistry , Molecular Structure , Protein Structure, SecondaryABSTRACT
Inhibition of protein-protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads--and how criteria applied to these may differ from conventional small-molecule drugs--are summarized.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Protein Interaction Maps/drug effects , Proteins/antagonists & inhibitors , Proteins/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Protein Binding/drug effects , Protein Structure, Secondary , Proteins/chemistry , Signal Transduction/drug effectsABSTRACT
The design and synthesis of a new 2-O-alklyated benzamide α-helix mimetic is described. Comparison with regioisomeric 3-O-alkylated benzamides permits a preliminary evaluation of the role that mimetic curvature has in determining molecular recognition properties.
Subject(s)
Benzamides/chemistry , Alkylation , Biomimetics , Drug Design , Inhibitory Concentration 50 , Models, Molecular , Molecular MimicryABSTRACT
A new series of simple endoperoxides, characterized by a 3-methoxy-1,2-dioxane scaffold, was designed on the basis of a previously developed pharmacophore. Through a simplified and versatile scheme of synthesis, which utilizes cheap and commercially available starting materials, it was possible to obtain several structurally and stereochemically different compounds that were tested against P. falciparum. Most of compounds showed antimalarial activity in the low micromolar range and no cellular toxicity, all being significantly more active on chloroquine resistant (CQ-R) than on chloroquine sensitive (CQ-S) strains. Resulting structure-activity relationships were analyzed by means of experimental and computational techniques, validating our design rationale and tailoring it for the new scaffold. Our study demonstrated that according to the hypothesized mechanism of action, the antimalarial activity can be improved through rational structural modifications, paving the way for the development of new simplified antimalarial endoperoxides.
