Targeting Protein-Protein Interaction by Small Molecules

Jin, Lingyan; Wang, Weiru; Fang, Guowei

doi:10.1146/annurev-pharmtox-011613-140028

Cited by 173 publications

(138 citation statements)

References 114 publications

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“…Yet there is increasing evidence that small molecules that effectively dock onto hotspots of the interaction sites between partners and thus inhibit their interactions can indeed be found (reviewed in ref. 48). Such hotspots have been reported for the b-catenin/TCF4 interaction (32,37).…”

Section: Discussionmentioning

confidence: 99%

A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

et al. 2016

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Wnt/b-catenin signaling is a highly conserved pathway essential for embryogenesis and tissue homeostasis. However, deregulation of this pathway can initiate and promote human malignancies, especially of the colon and head and neck. Therefore, Wnt/b-catenin signaling represents an attractive target for cancer therapy. We performed high-throughput screening using AlphaScreen and ELISA techniques to identify small molecules that disrupt the critical interaction between b-catenin and the transcription factor TCF4 required for signal transduction. We found that compound LF3, a 4-thioureido-benzenesulfonamide derivative, robustly inhibited this interaction. Biochemical assays revealed clues that the core structure of LF3 was essential for inhibition. LF3 inhibited Wnt/b-catenin signals in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. LF3 also suppressed features of cancer cells related to Wnt signaling, including high cell motility, cell-cycle progression, and the overexpression of Wnt target genes. However, LF3 did not cause cell death or interfere with cadherinmediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentrationdependent manners, as examined by sphere formation of colon and head and neck cancer stem cells under nonadherent conditions. Finally, LF3 reduced tumor growth and induced differentiation in a mouse xenograft model of colon cancer. Collectively, our results strongly suggest that LF3 is a specific inhibitor of canonical Wnt signaling with anticancer activity that warrants further development for preclinical and clinical studies as a novel cancer therapy. Cancer Res; 76(4); 891-901. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

et al. 2016

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“…Therapeutic targeting of PPIs offers an attractive alternative to classical drug targets in cases where the target of interest does not exhibit any enzymatic activity or ligand binding site that can be easily targeted and because of the large number of potential PPI targets (39). Indeed PPIs represent an emerging class of drug targets and there is a growing interest in technologies that allow screening for small molecule disruptors of PPIs.…”

Section: Discussionmentioning

confidence: 99%

Kinase Substrate Sensor (KISS), a Mammalian In Situ Protein Interaction Sensor

Lievens

Gerlo

Lemmens

et al. 2014

Molecular & Cellular Proteomics

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Probably every cellular process is governed by proteinprotein interaction (PPIs), which are often highly dynamic in nature being modulated by in-or external stimuli. Here we present KISS, for KInase Substrate Sensor, a mammalian two-hybrid approach designed to map intracellular PPIs and some of the dynamic features they exhibit. Benchmarking experiments indicate that in terms of sensitivity and specificity KISS is on par with other binary protein interaction technologies while being complementary with regard to the subset of PPIs it is able to detect. We used KISS to evaluate interactions between different types of proteins, including transmembrane proteins, expressed at their native subcellular location. In situ analysis of endoplasmic reticulum stress-induced clustering of the endoplasmic reticulum stress sensor ERN1 and ligand-dependent ␤-arrestin recruitment to GPCRs illustrated the method's potential to study functional PPI modulation in complex cellular processes. Exploring its use as a tool for in cell evaluation of pharmacological interference with PPIs, we showed that reported effects of known GPCR antagonists and PPI inhibitors are properly recapitulated. In a three-hybrid setup, KISS was able to map interactions between small molecules and proteins. Taken A protein's function is largely mediated through its interactions with other proteins, hence the critical importance of protein-protein interaction (PPI) 1 maps for understanding cellular mechanisms of action in health and disease. Whereas many proteins are organized in stable multi-protein complexes, the majority of cellular processes are governed by transient protein encounters, the dynamics of which are directed by a diversity of both intra-and extracellular signals. Our view of protein networks is still, however, mainly a static one (1). Current interactomes consist mainly of data generated by yeast 2-hybrid (Y2H) (2) and (tandem) affinity purification combined with mass spectrometry (3) and should be interpreted as scaffolds of potential PPIs that might occur at a certain time and place in the cell or as snapshots of PPIs taking place under a specific cellular condition. Although very robust and highly efficient, these approaches do not allow

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“…The GPCR-TRP Axis protein-protein interactions have had limited success owing to difficulty in disrupting the large interfaces between interacting proteins (Jin et al, 2014). However, several approaches that have been explored to disrupt such interactions may allow for TRP channelspecific inhibition.…”

Section: Therapeutic Targeting Of G Protein-coupled Receptor-transmentioning

confidence: 99%

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

Veldhuis¹,

Poole²,

Grace³

et al. 2014

Pharmacol Rev

133

135

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Targeting Protein-Protein Interaction by Small Molecules

Cited by 173 publications

References 114 publications

A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

Kinase Substrate Sensor (KISS), a Mammalian In Situ Protein Interaction Sensor

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

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