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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 A DNA-Encoded Combinatorial Library of Macrocyclic Peptoids Targeting Skp2

등록일
2019년 8월 29일 10시 42분 42초
접수번호
1773
발표코드
LIFE.O-3 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
발표시간
목 09시 : 30분
발표형식
구두발표
발표분야
Life Chemistry - Oral Presentations by Young Life Chemists
저자 및
공동저자
Min Hyeon Shin, Hyun-Suk Lim*
Department of Chemistry, Pohang University of Science and Technology, Korea
Skp2 is frequently overexpressed in many human cancers and considered as a proto-oncogene. It is believed that Skp2 has two critical roles in tumorigenesis. The first role of Skp2 is related with proteolytic function. As a component of the SCFSkp2 ubiquitin E3 ligase complex, Skp2 derives the cell cycle by mediating the proteasomal degradation of key cell cycle proteins. The second role is non-proteolytic function which suppresses p53-dependent apoptosis by outcompeting p53 for binding to histone acetyltransferase p300, thereby perturbing p300-mediated p53 acetylation and leading to tumorigenesis. As a result, inhibition of Skp2 functions is emerging as a promising and novel anti-cancer strategy. In this study, we constructed a DNA-encoded one-bead one-compound cyclic peptoid library with a vast theoretical diversity of 1.13ⅹ107. The library was screened against Skp2 protein using FACS-based high-throughput screening method. We discovered cyclic peptoid inhibitors that directly bind to Skp2. The binding of inhibitors was confirmed in fluorescence polarization assay, and these inhibitors decreased the level of p53 and acetylated-p53 which is related with non-proteolytic function of Skp2. Our results suggest that FACS-based high-throughput screening with DNA-encoded library can be used as useful tool to get many potential hit structure of target protein, and identified Skp2 inhibitors have great potential as a chemical probe to investigate Skp2 functions and as novel drug candidates for anticancer therapy.

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