Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

[Display omitted] Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. Th...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-02, Vol.28 (3), p.523-528
Main Authors: Whiting, Ellis, Raje, Mithun R., Chauhan, Jay, Wilder, Paul T., Van Eker, Daniel, Hughes, Samuel J., Bowen, Nathan G., Vickers, Gregory E.A., Fenimore, Ian C., Fletcher, Steven
Format: Article
Language:English
Subjects:
Apoptosis
Bcl-xL
Cancer
Mcl-1
Protein-protein interaction
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Summary:[Display omitted] Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a Ki of 155 nM. Further investigation revealed comparable inhibition of Bcl-xL (Ki = 90 nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.11.023