N6-substituted adenosine analogues, a novel class of JAK2 inhibitors, potently block STAT3 signaling in human cancer cells.

The JAK2/STAT3 signaling pathway plays a critical role in oncogenesis and malignancy, which makes it a promising anticancer target. We report four N(6)-substituted adenosine analogues (AAs) as potential JAK2/STAT3 inhibitors identified through a STAT3-based high-throughput drug screening system. These AAs exhibited selective anti-cancer activity on human cancer cells and xenograft tumors with constitutively activated STAT3. They rapidly and potently suppressed constitutive and IL-6/IFN-γ-induced JAK2/STAT3 signal activation. In addition, we finally proved that the STAT3 signal blockage by three of these AAs was dependent on specific JAK2 inhibition. These AAs may represent new targeted therapeutic agents for JAK2/STAT3 hyper-activated human cancers.