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Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold
Ellis Whiting1, Mithun R Raje2, Jay Chauhan2
1School of Chemistry, University of Cardiff, Cardiff CF10 3AT, UK.
Abstract:
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.
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