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SYM-A5 : Chemoproteomics for Drug Development

오거나이저: 박종배(국립암센터)

함흥식(Emory University, USA) / 장영태(포항공과대학교) / 최환근(보로노이)



함흥식
Speaker
함흥식   CV
Affiliation
Emory University, USA
Title
Past, Present and Future of Chemoproteomics for Drug and Biomarker Discovery by Development of Novel Covalent Chemistry Probes
Abstract

Covalnet chemistry probes serves as valuable tools to investigate functions of proteins and to discover ligandability of proteins of interest. Despite efforts to expand toolbox of covalent chemisty probes for chemical proteomics (e.g., cysteine, lysine, and modified amino acid residues by post-translatinal modifications), the proteoforms remains inaccessible with limited number of covalent chemistry probes developed over the last two decades. Here, we introduce novel covalent probes (HHS-465, 475, and 482) named sulfur-triazole exchange (SuTEx) chemistry to target tyrosine and lysine residues with broad applications for chemical proteonmics. Furthermore, covalent fragment-based ligand discovery (cFBLD) was performed in live cells to identify cell-active ligands. HHS-0701 was identified as a prostaglandin reductase 2 (PTGR2) ligand which inhibits capable of blocking biochemical activity of PTGR2. Ultimately, a set of pan-kinase probes was developed by application of SuTEx chemistry to investigate change of kinase activity in live cells. Collectively, we describe SuTEx as a novel covalent chemistry for chemical biology to study the human proteome.

 

장영태
Speaker
장영태   CV
Affiliation
포항공과대학교 (POSTECH)
Title
Strategy for live cell distinction by fluorescent imaging probe
Abstract

Discrimination of each cell type in multicellular organism is the most important first step to figure out the complex cell community and control their regulation. The current gond-standard method of cell distinction is through established antibodies for biomarkers on the cell surface. To surrogate the antibodies, we have developed small fluorescent probes for live cell distinction. In addition to the conventional binding targets i.e. proteins and carbohydrates: Protein Oriented Live-cell Distinction (POLD) and Carbohydrate Oriented Live-cell Distinction (COLD), we have extended the scope of biomarkers to transporters, via Gating Oriented Live-cell Distinction (GOLD) and lipid composition of the cell membrane, via Lipid Oriented Live-cell Distinction (LOLD). The intrinsically complex nature of life requires further orthogonal strategy for higher dimension of cell discrimination. Recently, we further expanded to novel chemical biology approach of Metabolism Oriented Live-cell Distinction (MOLD) to enrich the toolboxes and strategy choice. The design and mechanism elucidation for various immune cells will provide the new insight for cell selective probe development. Eventually, the multi-dimensional layer of cell distinction strategy will be the basis of characterizing extremely complex cell communities

 

최환근
Speaker
최환근   CV
Affiliation
보로노이
Title
Chemically induced degradation of kinases by proteolysis targeting chimeras(PROTACs)
Abstract

To date, about 74 small-molecule kinse inhibitors were approved by the US Food and Drug Administration. Most of kinase inhibitors modulate cell signalling by catalzying the phosphorylation relevant prteins. Targeted protein degradation (TPD) shows promise for drug development that have historically been highly challenging to target with conventional small molecules. Heterobifunctional molecules that recruit E3 ubiquitin ligases for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. By using a multi-targeted kinase degrader, we rapidly discovered degradable kinase targets of therapeutic importance and then demonstrated how more selective degraders can be efficiently generated.