Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2
- Authors
- Kim, Min Young; Na, Insung; Kim, Ji Sook; Son, Seung Han; Choi, Sungwoo; Lee, Seol Eui; Kim, Ji-Hun; Jang, Kiseok; Alterovitz, Gil; Chen, Yu; van der Vaart, Arjan; Won, Hyung-Sik; Uversky, Vladimir N.; Kim, Chul Geun
- Issue Date
- Nov-2019
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Citation
- SCIENCE ADVANCES, v.5, no.11, pp.2375 - 2548
- Indexed
- SCIE
SCOPUS
- Journal Title
- SCIENCE ADVANCES
- Volume
- 5
- Number
- 11
- Start Page
- 2375
- End Page
- 2548
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/12337
- DOI
- 10.1126/sciadv.aav9810
- ISSN
- 2375-2548
- 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.
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