한빛사논문
- 조회2,704
Min Young Kim1,*, Insung Na2,*,†, Ji Sook Kim1,3, Seung Han Son1, Sungwoo Choi1, Seol Eui Lee1, Ji-Hun Kim4, Kiseok Jang3, Gil Alterovitz5, Yu Chen2, Arjan van der Vaart6, Hyung-Sik Won7,‡, Vladimir N. Uversky2,8,‡ and Chul Geun Kim1,‡
1 Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Korea.
2 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
3 Department of Pathology, Hanyang University College of Medicine, Seoul 04763, Korea.
4 College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
5 Boston Children's Hospital/Harvard Medical School, Boston, MA 02115, USA.
6 Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
7 Department of Biotechnology, Konkuk University, Chungju, Chungbuk 27478, Korea.
8 Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia.
* These authors contributed equally to this work.
† Present address: Boston Children’s Hospital/Harvard Medical School, Boston, MA 02115, USA.
‡ Corresponding author : Hyung-Sik Won, Vladimir N. Uversky, Chul Geun Kim
Abstract
Although intrinsically disordered protein regions (IDPRs) are commonly engaged in promiscuous protein-protein interactions (PPIs), using them as drug targets is challenging due to their extreme structural flexibility. We report a rational discovery of inhibitors targeting an IDPR of MBD2 that undergoes disorder-to-order transition upon PPI and is critical for the regulation of the Mi-2/NuRD chromatin remodeling complex (CRC). Computational biology was essential for identifying target site, searching for promising leads, and assessing their binding feasibility and off-target probability. Molecular action of selected leads inhibiting the targeted PPI of MBD2 was validated in vitro and in cell, followed by confirming their inhibitory effects on the epithelial-mesenchymal transition of various cancer cells. Identified lead compounds appeared to potently inhibit cancer metastasis in a murine xenograft tumor model. These results constitute a pioneering example of rationally discovered IDPR-targeting agents and suggest Mi-2/NuRD CRC and/or MBD2 as a promising target for treating cancer metastasis.
논문정보
- Research article
- 2019년 11월 (BRIC 등록일 2019-12-02)
- 국내(교신)+국외 연구진
- 생명과학 > 분자생물학
관련 보도자료
- Chosun Biz
- 2019. 11. 29
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