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  • 09월 10일 16시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능

제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Targeted Protein Degradation via the N-End Rule Pathway

2019년 9월 2일 20시 36분 19초
MEDI.O-2 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
목 09시 : 15분
Medicinal Chemistry - Oral Presentation of Young Discovery Chemists
저자 및
Yeongju Lee, Hyun-Suk Lim*
Department of Chemistry, Pohang University of Science and Technology, Korea
PROteloysis TArgeting Chimera (PROTAC) technology has emerged as a therapeutic strategy to degrade proteins related to diseases. However, developed PROTAC molecules only target a limited number of E3 ligases, thereby being applicable to specific cell lines that express PROTAC targeted E3 ligases. To be widely applicable in various cell lines, we designed a new concept of heterobifunctional degraders using N-end rule pathway without identification of new E3 ligases and selective ligands of the identified E3 ligases. The new degradation system couples N-degrons, which are degradation signals (degrons) in protein N-terminus, with the ligands of target proteins. To demonstrate feasibility of our strategy, we conjugated N-degrons to the previously reported cell-permeable stapled peptide yl-21 to be recognized as degradation signals resulting in ubiquitination and degradation of target protein NCOA1. We successfully demonstrated that the resultant compound exhibited proteasome-dependent degradation of NCOA1 while PROTAC molecules had no degradation effect. Furthermore, we examined that the designed compound depleted NCOA1 inducing the repression of breast cancer cells migration and invasion in vitro and in vivo. This new concept of chemical degraders will serve a widely applicable degradation method for targeting disease-related proteins and provide a strategy for new therapeutics. Reference [1] Lee, Y.; Yoon, H.; Hwang, S. M.; Shin, M. K.; Lee, J. H.; Oh, M.; Im, S. H.; Song, J.; Lim, H. S.; “Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction” J. Am. Chem. Soc. 2017, 139, 16056