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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.

Author information

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.

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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