Abstract / Summary
The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathways mediate signaling by multiple cytokines and growth factors critical for inflammation and immune regulation. Povorcitinib (INCB054707) is an oral JAK1 inhibitor designed to achieve high selectivity over JAK2 and minimize off-target hematologic effects. This study comprehensively assessed the in vitro selectivity and potency of povorcitinib relative to the JAK inhibitors upadacitinib, abrocitinib, baricitinib, and tofacitinib. Povorcitinib and comparator compounds were characterized using enzymatic assays, full kinome profiling across 370 kinases, cytokine reporter assays, human whole-blood STAT phosphorylation assays, and cell viability studies. Povorcitinib demonstrated potent, selective JAK1 inhibition with minimal activity against JAK2, JAK3, and TYK2, showing ≥ 50-fold selectivity over JAK2 in most assays, exceeding that of other JAK inhibitors. Kinome screening confirmed minimal off-target activity. In cell-based assays, povorcitinib selectively inhibited interleukin (IL)-6– and IL-2–mediated JAK1 signaling with minimal inhibition of thrombopoietin (TPO)-mediated JAK2 signaling, achieving up to 52-fold functional JAK1 selectivity in cytokine reporter assays and greater than tenfold selectivity in human whole blood. In contrast, other selective JAK1 inhibitors, such as upadacitinib, displayed near-equipotent JAK1/JAK2 inhibition in whole-blood assays. Povorcitinib displayed no cytotoxicity at concentrations > 5000 nM in HEK293, HEPG2, HUVEC, and HLF cells, which are JAK-independent. Across orthogonal assays, povorcitinib consistently exhibited the highest JAK1 selectivity among the JAK inhibitors evaluated. These data, together with its favorable pharmacokinetic and emerging clinical safety profile, highlight the potential for povorcitinib as a highly selective, next-generation JAK1 inhibitor.