HDAC inhibitors as anticancer drugs: chemical diversity, clinical trials, challenges and perspectives

In an attempt to collect clinical data about HDAC inhibitors as very significant anticancer drugs we aimed to compare data and reveal the impact of the structural features, concluding the points of interest that are likely to help further development of better cancer therapy. We presented results of different clinical phases of HDAC inhibitors classified as hydroxamic acid derivatives, cyclic peptides, benzamides, and short chain aliphatic acids in a coherent and cohesive manner. It was found that HDAC inhibitors are preferentially combined with other antitumor drugs, mainly anti PD-1 and doxorubicin. In contrast, drugs such as docetaxel exaggerate the toxicity of HDAC inhibitors. Furthermore, data from clinical trials showed that the efficacy of HDAC inhibitors as single agents was limited against solid tumors. But they were significant against many solid tumors when combined with other anticancer agents. For example, combination of vorinostat and doxorubicin showed good results in solid tumors, especially prostate cancer, breast cancer, and melanoma. On the contrary, single agents of HDAC inhibitors revealed considerable clinical outcomes against different types of lymphoma and leukemia that warrant further investigation. Meanwhile, combinations of HDAC inhibitors and other drugs were also effective against lymphomas and leukemias.