BET Isoform Selectivity through Diverse Linkers for Bivalent Inhibitors: GSK785, a BRD2/4-Selective Bivalent BET Inhibitor

The inhibition of the Bromodomain and Extra Terminal (BET) family of proteins has been widely studied for over a decade for its potential therapeutic benefit in cancer and immuno-inflammatory diseases. Selective inhibition within the four BET isoforms has been sought to facilitate the understanding of the individual role played by each family member and to mitigate pharmacologically driven tolerability limitations observed in the clinic for pan-BET inhibitors. Herein, we present an investigation into the potential for isoform selectivity using bivalent inhibitors with constrained linker geometries. By employing a set of conformationally restricted diamines as linkers between two BET-binding warheads, this work details the design and synthesis of two iterations of bivalent molecules. While finding the BET isoforms to be highly accommodating of bivalent molecules with diverse linker geometries, we present the discovery of <b>9h</b> (GSK785), a bivalent inhibitor with an unprecedented BRD2/4-selective, BRD3 sparing profile.