In recent studies, combinations of histone deacetylases (HDACs) inhibitor with kinase inhibitor showed additive and synergistic effects. BRaf V600E as an attractive target in many diseases treatments has been studied extensively. Herein, we present a novel design approach though incorporating the pharmacophores of BRaf V600E inhibitor and HDACs inhibitor in one molecule. Several synthesized compounds exhibited distinct BRaf V600E and HDAC1 inhibitory activities. The representative dual Raf/HDAC inhibitor, 7a, showed better antiproliferative activities against A549 and SK-Mel-2 in cellular assay than SAHA and sorafenib, with IC 50 values of 9.11 µM and 5.40 µM, respectively. This work may lay the foundation for the further development of dual Raf/HDAC inhibitors as potential anticancer agents.

Histone deacetylases (HDACs) as attractive targets in many diseases therapies has been studied extensively, and its application in cancer research is the most important. Here, we developed a series of derivatives containing natural 2,5-diketopiperazine (DKP) skeleton. Several compounds exhibited distinct HDAC1 inhibitory activities, in particular 2a (IC 50 405 nM). The selectivity profile for representative 2a indicated that this series of compounds had a preference for HDAC1-3. Additionally, 2a showed the best growth inhibitory activities against K562 and HL-60 tumor cell line with IC 50 values of 4.23 and 4.16 µM, respectively. This work may lay the foundation for developing DKP-based HDAC inhibitors as a potential anticancer agent.

Histone deacetylases (HDACs) are important targets in cancer treatment, and the development of selective and broad-spectrum HDACs inhibitors (HDACis) is urgent. In this research, a series of aroylpiperazine hybrid derivatives were designed and synthesized. Among these, indole-piperazine hybrids 6a (IC 50 205 nM) and 6b (IC 50 280 nM) showed submicromolar activity against HDAC1. Moreover, 6a showed a preferable affinity toward class I HDACs, especially for HDAC1-3. In vitro, 6a exhibited better antiproliferative activities against K562 and HCT116 cell lines than chidamide.