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  • 08월 28일 16시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능

A small molecular scaffold for selective inhibition of Wip1 phosphatase

2008년 8월 11일 16시 46분 00초
33P191포 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
목 <발표Ⅰ>
저자 및
박은식, 원미숙1, 윤장희1, 김종필1, 김석만, 강신원, 방정규1
부산대학교 화학과, Korea
1한국기초과학지원연구원 부산센터, Korea
The phosphatase Wip1 indirectly suppresses the activity of the turmor suppressor protein p53. After DNA damage, such as ionizing radiation or UV light, several cellular pathways combine to increase the activity of p53, which in turn controls cell cycle arrest and apoptosis. Within the network of p53 activation, Wip1 inactivates p38 MAP kinase via dephosphorylation of a phosphothreonine. In its own role, phosphorylated p38 MAP kinase phosphorylates and activates p53. Therefore, Wip1 controls a negative feedback loop within the p38 MAP kinase-p53 signaling pathway. Overexpression of Wip1 protein has been observed in several cancer, including breast cancer, neuroblastoma, and ovarian clear cell adenocarcinoma. The data accumulated about the biological functions of Wip1 indicated that inhibition of its enzymatic activity could be an effective strategy for combating certain types of cancer. Using a pyrrole-based scaffold, we developed a series of small molecules that mimic the three-dimensional arrangement of the polar and hydrophobic functional groups of the best cyclic-peptide inhibitor. Iterative optimization cycles of design, synthesis, and kinetic testing has lead to a selective inhibitor of Wip1. The picture shows the structure of the best inhibitor bound to the active site of the enzyme.