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Sci Adv. 2019 Nov 20;5(11):eaav9810. doi: 10.1126/sciadv.aav9810. eCollection 2019 Nov.

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

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Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Korea.
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Department of Pathology, Hanyang University College of Medicine, Seoul 04763, Korea.
College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Korea.
Boston Children's Hospital/Harvard Medical School, Boston, MA 02115, USA.
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Department of Biotechnology, Konkuk University, Chungju, Chungbuk 27478, Korea.
Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia.


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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