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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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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cited_by cdi_FETCH-LOGICAL-c356t-e6aa9735402d9605e8100db2993234d01ffcba8a2b584a52e40cae897c748eb3
cites cdi_FETCH-LOGICAL-c356t-e6aa9735402d9605e8100db2993234d01ffcba8a2b584a52e40cae897c748eb3
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container_issue 3
container_start_page 523
container_title Bioorganic & medicinal chemistry letters
container_volume 28
creator 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
description [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.
doi_str_mv 10.1016/j.bmcl.2017.11.023
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subjects Apoptosis
Bcl-xL
Cancer
Mcl-1
Protein-protein interaction
title Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold
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