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| Type |
Poster Presentation |
| Area |
Life Chemistry |
| Room No. |
Exhibition Hall 2 |
| Time |
4월 19일 (금요일) 11:00~12:30 |
| Code |
LIFE.P-361 |
| Subject |
Development of HSP90β Proteolysis Targeting Chimera (PROTAC) Protein Degrader |
| Authors |
YeongMok Kim, Sang Jeon Chung1,*
Sungkyunkwan University, Korea
1College of Pharmacy, SungKyunKwan University, Korea
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| Abstract |
In general, therapeutic strategies focus on the use of small molecules to influence the activity of disease-related proteins. However, there is an increasing demand for the development of new approaches to overcome the limitations of previously developed drugs as well as in the treatment of "undruggable targets". Here, a new concept coined PROTAC that aims to selectively induce proteolytic degradation of disease-related proteins is presented.
The 26S proteasome is the main pathway for regulated degradation of cellular proteins in all eukaryotic organisms. The high specificity of the 26S proteasome is attributed to the ubiquitin (UB) pathway, thus for a protein to be degraded it must be ubiquitylated. The sequential action of three enzymes E1 (UB-activating), E2 (UB-conjugating), and E3 (UB-ligases) are necessary to attach UB to a target protein.
Our strategy involves the recruitment of E3 to tag a specific target protein for degradation by the 26S proteasome. To achieve this, a molecular probe comprising a known E3 ligand tethered to a target specific ligand is constructed. Heat shock protein 90 (HSP90), involved in the division and survival of cancer cells was selected as the target of interest. Typical HSP90 inhibitors bind to the ATP-binding domain and affects the HSP90 chaperone cycling. However, the therapeutic application of HSP90 drugs are hampered due to solubility and hepatotoxicity issues. It is believed that the here presented PROTAC technology is a good alternative to selectively degrade HSP90 and is a viable new therapeutic approach.
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| E-mail |
rusynante@naver.com |
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123rd General Meeting of the KCS