Discovery and evaluation of Atopaxar hydrobromide, a novel JAK1 and JAK2 inhibitor, selectively induces apoptosis of cancer cells with constitutively activated STAT3

Summary The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a vital role in immunity, cell division, cell death and tumor formation. Disrupted JAK-STAT signaling may lead to various diseases, especially cancer and immune disorders. Because of its importance, this signaling pathway has received significant attention from the pharmaceutical and biotechnology industries as a therapeutic target for drug design. However, few JAK or STATs inhibitors have been developed for cancer treatment. We used an in vitro STAT3 luciferase reporter assay to find novel inhibitors that could effectively block the JAK-STAT pathway. In our study, we screened 16,081 drug-like chemicals and found that atopaxar hydrobromide (AHB) is a specific inhibitor of JAK-STAT3 signaling. Our results suggest that AHB not only blocks constitutively activated and cytokine-induced STAT3 phosphorylation but also inhibits JAK1 and JAK2 phosphorylation. Moreover, AHB induces G1 phase cell cycle arrest, which stops cancer cell growth and induces apoptosis. AHB also inhibited tumor cell growth in vivo. In conclusion, AHB is a potential inhibitor that could be developed as a JAK-STAT pathway drug.