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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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Citation / Publisher Attribution
Science Advances, v. 5, issue 11, art. eaav9810
Scholar Commons Citation
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 Vaar, Arjant; Won, Hyung-Sik; Uversky, Vladimir N.; and Kim, Chul Geun, "Rational Discovery of Antimetastatic Agents Targeting the Intrinsically Disordered Region of MBD2" (2019). Molecular Medicine Faculty Publications. 818.