4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads

Abstract

Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor <b>XD14</b> and well-established HDAC inhibitors. The most promising new hybrids, <b>49</b> and <b>61</b>, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. <b>49</b> induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, <b>61</b>, induced significantly more apoptosis than the related control compounds <b>62</b> (no BRD4(1) affinity) and <b>63</b> (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, <b>61</b> was well tolerated in an <i>in vivo</i> zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.