Rational Discovery of Antimetastatic Agents Targeting the Intrinsically Disordered Region of MBD2
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Kim, Ji Sook
Son, Seung Han
Choi, Sungwoo
Lee, Seol Eui
Kim, Ji-Hun
Jang, Kiseok
Chen, Yu
van der Vaart, Arjan
Won, Hyung-Sik
Uversky, Vladamir
Kim, Chul Geon
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https://doi.org/10.1126/sciadv.aav9810Metadata
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Kim, 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.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867884/Citable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373058
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