Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small-molecule proteomimetic inhibitors of the HIF-1?-p300 protein-protein interaction.

ABSTRACT: The therapeutically relevant hypoxia inducible factor HIF-1?-p300 protein-protein interaction can be orthosterically inhibited with ?-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1? C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1?-p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF-1?, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1? C-TAD from which it is derived.

SUBMITTER: Burslem GM

PROVIDER: S-EPMC4159589 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Small-molecule proteomimetic inhibitors of the HIF-1α-p300 protein-protein interaction.

Burslem George M GM Kyle Hannah F HF Breeze Alexander L AL Edwards Thomas A TA Nelson Adam A Warriner Stuart L SL Wilson Andrew J AJ

Chembiochem : a European journal of chemical biology 20140429 8

The therapeutically relevant hypoxia inducible factor HIF-1α-p300 protein-protein interaction can be orthosterically inhibited with α-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1α C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characteris ...[more]

PMID: 24782431

Similar Datasets

Anticancer osmium complex inhibitors of the HIF-1? and p300 protein-protein interaction.

Project description:The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1?-p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1?-p300 interaction. We evaluated the effect of complex 1 on HIF-1? signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22??M. Complex 1 interfered with the HIF-1?-p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1? as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-?B. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1? inhibitors for anti-cancer treatment.

| S-EPMC5320473 | biostudies-other

Oligobenzamide proteomimetic inhibitors of the p53-hDM2 protein-protein interaction.

Project description:Oligobenzamide inhibitors of the p53-hDM2 protein-protein interaction are described.

| S-EPMC2898631 | biostudies-literature

Recent Small-Molecule Inhibitors of the p53-MDM2 Protein-Protein Interaction.

Project description:This review presents the last decade of studies on the synthesis of various types of small-molecule inhibitors of the p53- Mouse double minute 2 homolog (MDM2) protein-protein interaction. The main focus is placed on synthetic approaches to such molecules, their cytotoxicity, and MDM2 binding characteristics.

| S-EPMC7179467 | biostudies-literature

Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction.

Project description:Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1-TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein-protein interactions, establish the structural requirements needed for efficient CD40-CD40L inhibition, and serve to guide the search for such immune therapeutics.

| S-EPMC5823691 | biostudies-literature

AnchorQuery: Rapid online virtual screening for small-molecule protein-protein interaction inhibitors.

Project description:AnchorQuery (http://anchorquery.csb.pitt.edu) is a web application for rational structure-based design of protein-protein interaction (PPI) inhibitors. A specialized variant of pharmacophore search is used to rapidly screen libraries consisting of more than 31 million synthesizable compounds biased by design to preferentially target PPIs. Every library compound is accessible through one-step multi-component reaction (MCR) chemistry and contains an anchor motif that is bioisosteric to an amino acid residue. The inclusion of this anchor not only biases the compounds to interact with proteins, it also enables a rapid, sublinear time pharmacophore search algorithm. AnchorQuery provides all the tools necessary for users to perform online interactive virtual screens of millions of compounds, including pharmacophore elucidation and search, and enrichment analysis. Accessibility: AnchorQuery is freely accessible at http://anchorquery.csb.pitt.edu.

| S-EPMC5734307 | biostudies-literature

High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.

Project description:Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.

| S-EPMC5180416 | biostudies-literature

Small-Molecule Inhibitors of the NusB-NusE Protein-Protein Interaction with Antibiotic Activity.

Project description:The NusB-NusE protein-protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified N,N'-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 1 as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated 1 as a 20 μM potent inhibitor of NusB-NusE. Four focused compound libraries based on 1, comprising 34 compounds in total were designed, synthesized, and evaluated as NusB-NusE PPI inhibitors. Ten analogues displayed NusB-NusE PPI inhibition ≥50% at 25 μM concentration in vitro. In contrast to representative Gram-negative Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 μM. 2-((Z)-4-(((Z)-4-(4-((E)-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and ≤51 μg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB-NusE PPI as proposed.

| S-EPMC6044933 | biostudies-literature

Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1?/p300 Interaction.

Project description:Inhibition of the hypoxia-inducible factor 1? (HIF-1?) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1?/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1?/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1?/p300 binding, 170?298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 ?M). Luciferase assays confirmed inhibition of HIF-1? transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 ?M, p < 0.05). Except for 11, all of these compounds also reduced HIF-1? transcriptional activity in LNCaP prostate cancer cells (0.1-10 ?M, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1? target level, compound 8 (0.5 ?M) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1? inhibitors, which interrupt the protein-protein interaction between HIF-1? and p300 and consequently reduce HIF-related transcription.

| S-EPMC6323635 | biostudies-literature

Selective and Potent Proteomimetic Inhibitors of Intracellular Protein-Protein Interactions.

Project description:Inhibition of protein-protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. ?-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed "proteomimetics", which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.

| S-EPMC4737265 | biostudies-literature

Small Molecule Inhibitors of the PCSK9·LDLR Interaction.

Project description:The protein-protein interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) is a relatively new, and extremely important, validated therapeutic target for treatment and prevention of heart disease. Experts in the area agree that the first small molecules to disrupt PCSK9·LDLR would represent a milestone in this field, yet few credible leads have been reported. This paper describes how side-chain orientations in preferred conformations of carefully designed chemotypes were compared with LDLR side chains at the PCSK9·LDLR interface to find molecules that would mimic interface regions of LDLR. This approach is an example of the procedure called EKO (Exploring Key Orientations). The guiding hypothesis on which EKO is based is that good matches indicate the chemotypes bearing the same side chains as the protein at the sites of overlay have the potential to disrupt the parent protein-protein interaction. In the event, the EKO procedure and one round of combinatorial fragment-based virtual docking led to the discovery of seven compounds that bound PCSK9 (SPR and ELISA) and had a favorable outcome in a cellular assay (hepatocyte uptake of fluorescently labeled low-density lipoprotein particles) and increased the expression LDLR on hepatocytes in culture. Three promising hit compounds in this series had dissociation constants for PCSK9 binding in the 20-40 ?M range, and one of these was modified with a photoaffinity label and shown to form a covalent conjugate with PCSK9 on photolysis.

| S-EPMC6404525 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data