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Published on: May 15, 2019
Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2
Min Young Kim1, Insung Na2, Ji Sook Kim1,3
1Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Korea.
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.
Insights
Researchers rationally discovered inhibitors for intrinsically disordered protein regions (IDPRs), targeting MBD2 to block cancer metastasis. This approach successfully inhibited cancer cell transitions and tumor growth in preclinical models.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Intrinsically disordered protein regions (IDPRs) are challenging drug targets due to their flexibility.
- IDPRs are involved in numerous protein-protein interactions (PPIs).
- The MBD2 IDPR is crucial for the Mi-2/NuRD chromatin remodeling complex (CRC) and cancer metastasis regulation.
Purpose of the Study:
- To rationally discover inhibitors targeting the MBD2 IDPR.
- To validate the therapeutic potential of these inhibitors against cancer metastasis.
Main Methods:
- Computational biology for target identification and lead compound screening.
- In vitro and cellular assays to validate molecular action and PPI inhibition.
- In vivo studies using a murine xenograft tumor model to assess anti-metastatic efficacy.
Main Results:
- Identified and validated lead compounds inhibiting MBD2 PPI.
- Demonstrated inhibition of epithelial-mesenchymal transition in cancer cells.
- Showcased potent inhibition of cancer metastasis in a preclinical tumor model.
Conclusions:
- Pioneering example of rationally designed IDPR-targeting agents.
- MBD2 and the Mi-2/NuRD CRC are promising therapeutic targets for cancer metastasis.
