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SCI Article

Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2
성명 김철근()
소속 자연과학대학 생명과학과
캠퍼스
우수선정주 2019년 12월 3째주
Author Kim, Min Young (Dept Life Sci); Kim, Ji Sook (Dept Life Sci); Son, Seung Han (Dept Life Sci); Choi, Sungwoo (Dept Life Sci); Lee, Seol Eui (Dept Life Sci); 김철근 (Dept Life Sci); Kim, Min Young (Res Inst Nat Sci); Kim, Ji Sook (Res Inst Nat Sci); Son, Seun
Corresponding Author Info Kim, CG (reprint author), Hanyang Univ, Dept Life Sci, Seoul 04763, South Korea.; Kim, CG (reprint author), Hanyang Univ, Res Inst Nat Sci, Seoul 04763, South Korea.; Uversky, VN (reprint author), Univ S Florida, Dept Mol Med, Morsani Coll Med, Tampa, FL
E-mail 이메일 아이콘cgkim@hanyang.ac.kr
Document Type Article
Source SCIENCE ADVANCES Volume:5 Issue:11 Pages:- Published:2019
Times Cited 0
External Information http://dx.doi.org/10.1126/sciadv.aav9810
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.
Web of Science Categories Multidisciplinary Sciences
Funding Basic Science Research Program [2014R1A2A1A11054432, NRF-2017M3A9C8027975]; National Research Foundation (NRF); Hanyang University, Republic of Korea [HY-2018]; NSF MRINational Science Foundation (NSF)NSF - Office of the Director (OD) [CHE-1531590]
Language English
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