Biomedical subjects

Yongmun Choi

Publications and source records attributed to Yongmun Choi.

7 recordsLinked to original sources

PubMed2006

Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2.

Insulin-like growth factor 2 (IGF2) is a potent mitogen whose deregulation plays a role in developing liver, breast, and prostate cancers. Here, we take a small-molecule approach to investigate molecular pathways that modulate IGF2 signaling, by using chromeceptin, a synthetic molecule that selectively impairs the viability and growth of IGF2-overexpressing hepatocellular carcinoma cells. Affinity purification revealed that chromeceptin binds to multifunctional protein 2 (MFP-2), a seemingly multifunctional enzyme implicated in peroxisomal beta-oxidation. The small molecule-protein interaction stimulates the expression of IGF binding protein 1 (IGFBP-1) and suppressor of cytokine signaling-3 (SOCS-3), two cellular attenuators of the IGF signals, through activation of signal transducers and activators of transcription 6 (STAT6). The results underline the importance of STATs in IGF/insulin regulation, and they implicate a new pathway for STAT6 activation that is amenable to small-molecule intervention.

17-Hydroxysteroid Dehydrogenases↗

PubMed2006

Small organic molecules that modulate gene transcription.

Regulation of gene expression by transcription factors touches all aspects of human biology and often induces extreme phenotypes. Its external, precise control by small organic molecules represents a challenge in chemistry and biology. Here, we summarize recent progress in the field, together with contributions from our laboratory. Small-molecule modulators of transcription, including small-molecule transcription factors could find their use in basic biological studies and therapeutic intervention.

Adamantane↗

PubMed2004

Small molecule transcription factor mimic.

Regulation of gene expression by transcription factors touches many aspects of eukaryotic biology, and its systematic, external control by organic molecules represents a challenge in chemistry. Here we report the design of a completely organic, nonpeptidic compound that mimics a transcription factor. The design takes advantage of the specific DNA-binding affinity of a hairpin polyamide molecule and the ability of wrenchnolol to bind to the Sur-2 subunit of human mediator complex. The hybrid compound of these two molecules activates transcription of a reporter gene in vitro in a promoter-dependent manner through simultaneous contacts with DNA and Sur-2. Our results indicate that it is possible to generate a transcription factor out of nonpeptidic components.

Adamantane↗

PubMed2004

A wrench-shaped synthetic molecule that modulates a transcription factor-coactivator interaction.

Development of synthetic molecules that provide external control over the transcription of a given gene represents a challenge in medicinal and bioorganic chemistry. Here we report design and analysis of wrenchnolol, a wrench-shaped synthetic molecule that impairs the transcription of the Her2 oncogene by disrupting association of transcription factor ESX with its coactivator Sur-2. The "jaw" part of the compound mimics the alpha-helical interface of the activation domain of ESX, and the "handle" region accepts chemical modifications for a range of analysis. A water-soluble handle permitted NMR study in aqueous solution; a biotinylated handle verified the selectivity of the interaction, and a fluorescent handle confirmed the cell permeability of the compound. The case study of wrenchnolol foreshadows the promise and the challenge of targeting protein-protein interactions in the nucleus and may lead to the development of unique synthetic modulators of gene transcription.

Adamantane↗

PubMed2003

A gene-expression inhibitor that targets an alpha-helix-mediated protein interaction.

Protein-protein interactions are harder to target by small organic molecules than by enzymes or nuclear hormone receptors. Here we report the discovery of an organic compound that inhibits the expression of the Her2 oncogene by disrupting an alpha-helix-mediated protein interaction. The druglike molecule we named adamanolol competitively inhibited the interaction between the two cancer-linked nuclear proteins, ESX (an epithelial-specific transcription factor) and Sur-2/DRIP130 (a Ras-linked subunit of the human mediator complex), which is important for the overexpression of Her2 gene in malignant breast cancer cells. Adamanolol impaired Her2 expression and caused cell death selectively in Her2-positive breast cancer cells. NMR signals of adamanolol suggest that its rigid conformation plays a role in forming a helixlike surface for the interaction.

Adamantane↗

PubMed2002

Identification of bioactive molecules by adipogenesis profiling of organic compounds.

An important step in the postgenomic drug discovery is the construction of high quality chemical libraries that generate bioactive molecules at high rates. Here we report a cell-based approach to composing a focused library of biologically active compounds. A collection of bioactive non-cytotoxic chemicals was identified from a divergent library through the effects on the insulin-induced adipogenesis of 3T3-L1 cells, one of the most drastic and sensitive morphological alterations in cultured mammalian cells. The resulting focused library amply contained unique compounds with a broad range of pharmacological effects, including glucose-uptake enhancement, cytokine inhibition, osteogenesis stimulation, and selective suppression of cancer cells. Adipogenesis profiling of organic compounds generates a focused chemical library for multiple biological effects that are seemingly unrelated to adipogenesis, just as genetic screens with the morphology of fly eyes identify oncogenes and neurodegenerative genes.

3T3 Cells↗

PubMed2002

External control of Her2 expression and cancer cell growth by targeting a Ras-linked coactivator.

Overproduction of the Her2 oncoprotein has been found in approximately 30% of breast tumors, and patients who have Her2 excesses typically have more aggressive disease. Here we show that the expression of the Her2 gene can be decreased by inhibiting the interaction of the two cancer-linked proteins, DRIP130/CRSP130/Sur-2 (a Ras-linked subunit of human mediator complexes) and ESX (an epithelial-restricted transcription factor). Disruption of the interaction by a short cell-permeable peptide reduced the expression of the Her2 gene and specifically impaired the growth and viability of Her2-overexpressing breast cancer cells. The association of ESX with DRIP130 is mediated by a small hydrophobic face of an 8-aa helix in ESX, suggesting a therapeutic approach to incapacitating the Her2 gene by small organic molecules.

Amino Acid Sequence↗