HDAC/JAK dual target inhibitors of cancer-related targets: The success of nonclearable linked pharmacophore mode

Abstract

In recent years, the development of dual target drugs has become a research hotspot in cancer treatment and the reasonable design of the drugs is critical. The nonclearable linked pharmacophore mode is one of the commonly used strategies for designing dual target drugs, it can connect the pharmacophores of two synergistic target inhibitors into one molecule through the linker, which greatly improves the utilization of drugs. Epigenetic modifications as a potential treatment for multiple diseases have always been a subject of great concern, and Histone deacetylases (HDAC) plays an important role. Janus Kinase (JAK) is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-signal transducers and the activators of transcription (STAT) pathway. Studies showed the combination of HDAC and JAK inhibitors exhibited synergistic effects in breast cancer treatment [1]. In addition, the pharmacophore models of the aforementioned two inhibitors indicate similar essential features. Further investigation on recent years’ progress in the field demonstrated the nonclearable linked pharmacophore mode, using different length carbon chains as linkers to connect the pharmacophores of the two inhibitors, is the main strategy to design HDAC/JAK dual-target inhibitors which has been verified to be effective in biological activity tests. This review takes recent years’ HDAC/JAK dual target inhibitors’ development details as an example to summarize the general ideas behind the scene. We wish to provide the readers a theoretical basis for the development of more efficient dual-target or multi-target drugs in future.