Dual inhibitors of histone deacetylases and other cancer-related targets: A pharmacological perspective.

Epigenetic enzymes histone deacetylases (HDACs) are clinically validated anticancer drug targets which have been studied intensively in the past few decades. Although several drugs have been approved in this field, they are still limited to a subset of hematological malignancies (in particular T-cell lymphomas), with therapeutic potential not fully realized and the drug-resistance occurred after a certain period of use. To maximize the therapeutic potential of these classes of anticancer drugs, and to extend their application to solid tumors, numerous combination therapies containing an HDACi and an anticancer agent from other mechanisms are currently ongoing in clinical trials. Recently, dual targeting strategy comprising the HDACs component has emerged as an alternative approach for combination therapies. In this perspective, we intend to gather all HDACs-containing dual inhibitors related to cancer therapy published in literature since 2015, classify them into five categories based on targets' biological functions, and discuss the rationale why dual acting agents should work better than combinatorial therapies using two separate drugs. The article discusses the pharmacological aspects of these dual inhibitors, including in vitro biological activities, pharmacokinetic studies, in vivo efficacy studies, as well as available clinical trials. The review of the current status and advances should provide better analysis for future opportunities and challenges of this field.