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

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-JAK2^V617F 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.