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Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2

Title
Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2
Author
김철근
Keywords
COILED-COIL INTERACTION; PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; PROTEIN-PROTEIN; CPG ISLANDS; MYC-MAX; C-MYC; BINDING; PARALLEL; COMPLEX
Issue Date
2019-11
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Citation
SCIENCE ADVANCES, v. 5, no. 11, article no. eaav9810
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.
URI
https://advances.sciencemag.org/content/5/11/eaav9810https://repository.hanyang.ac.kr/handle/20.500.11754/155112
ISSN
2375-2548
DOI
10.1126/sciadv.aav9810
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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