DESIGN AND SYNTHESIS OF DUAL INHIBITORS OF JANUS KINASE AND HISTONE DEACETYLASE

Abstract

Genetic studies have found that a high percentage of patients with proliferative disorders have at least one type of epigenetic mutation. However, the treatment only with an epigenetic agent as well as the direct blocking of oncogenic signaling cascades is less effective as compared to established medications. To improve the efficiency of anticancer therapy, in this work, we propose a new molecular hybrid strategy which incorporates epigenetic agent with a signal transduction inhibitor. Such a multiple ligand agent is applicable against a range of proliferative diseases while the combination of a Janus kinase (JAK) binding motif with a histone deacetylase (HDAC) Zn-chelating group within a single molecule is potentially more effective in the treatment of proliferative diseases. The designed hybrid molecules lay the groundwork for efficient and highly potent dual JAK-HDAC inhibitors with surprising isoform selectivity are able to affect both signaling and epigenetic processes in proliferative diseases.