Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains

Abstract

<p class="first" id="d6579394e236"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/5aabb9df-b1fc-41aa-a58b-abee1130e945/PubMedCentral/image/ml-2017-00191d_0008"/> </div> </p><p id="d6579394e240">A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound <b>FT001</b>, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11). </p>