Na, InsungAlterovitz, GilKim, Min KyoungKim, Ji SookSon, Seung HanChoi, SungwooLee, Seol EuiKim, Ji-HunJang, KiseokChen, Yuvan der Vaart, ArjanWon, Hyung-SikUversky, VladamirKim, Chul Geon2022-08-252019-11Kim, Min Young, Insung Na, Ji Sook Kim, Seung Han Son, Sungwoo Choi, Seol Eui Lee, Ji-Hun Kim,Kiseok Jang, Gil Alterovitz, Yu Chen, Arjan Van Der Vaart, Hyung-Sik Won, Vladimir N. Uversky, and Chul Geun Kim. 2019. Rational Discovery of Antimetastatic Agents Targeting the Intrinsically Disordered Region of MBD2. Science Advances 5, no. 11: Eaav9810.2375-2548https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373058This work was mainly performed in University of South Florida in 2014 - 2017. But, it was recently submitted to Science Advances for the publication. I am the co-first author of this publication, and my PI (Gil Alterovitz) is involved as co-author.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.en-USJournal Article2022-08-2510.1126/sciadv.aav9810