The
feedback activation of the Janus kinase (JAK)–STAT pathway
leads to the fact that solid cancers are not sensitive to histone
deacetylase (HDAC) inhibitors. Herein, a series of novel 2-amino-4-phenylaminopyrimidine
JAK/HDAC dual-target inhibitors based on the moiety of fedratinib
were designed and synthesized. Among them, 21 and 30 potently inhibited HDAC3/6 and JAK1/2 at nanomolar levels
and exhibited splendid selectivity for the JAK2 against a panel of
76 kinases. 21 and 30 presented remarkable
antiproliferative activity in both hematological malignancies and
solid cancers, which was endorsed by JAK–STAT and HDAC pathway
blockade and proapoptotic activity. On the basis of great plasma stability
and oral bioavailability, 21 and 30 effectively
suppressed the tumor growth of HEL and A549 xenograft models. Collectively,
the above results validate that JAK/HDAC dual-target inhibitors provide
valuable clues for targeted treatment of hematological malignancies
and solid cancers.
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