The structure based design of dual HDAC/BET inhibitors as novel epigenetic probesElectronic supplementary information (ESI) available. See DOI: 10.1039/c3md00285c

Herein we describe the design and synthesis of a dual active histone deacetylase (HDAC)/bromodomain and extra terminal (BET) small molecule tool inhibitor, DUAL946 ( 1 ). Exploiting our extensive epigenetic toolbox, we achieved the functionalisation of a BET active tetrahydroquinoline (THQ) core, with a hydroxamic acid HDAC inhibitor (HDACi) motif. Dual inhibition of BET and HDAC proteins was confirmed by in vitro biochemical and biophysical testing and through chemoproteomic competition experiments in cell lysates. This activity was translated into potent cellular activity in both immune and cancer cells. DUAL946 (1) inhibits BET and HDAC proteins in chemoproteomic cell lysate experiments and in immune and cancer cells.