Design, synthesis and biological evaluation of purine-based derivatives as novel JAK2/BRD4(BD2) dual target inhibitors

Abstract

Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC50 values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/β signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3-JAK2V617F allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases.